EP3474900A1 - Dégradation de la protéine contenant un bromodomaine 9 (brd9) par conjugaison d'inhibiteurs de brd9 avec un ligand de la ligase e3 et procédés d'utilisation - Google Patents

Dégradation de la protéine contenant un bromodomaine 9 (brd9) par conjugaison d'inhibiteurs de brd9 avec un ligand de la ligase e3 et procédés d'utilisation

Info

Publication number
EP3474900A1
EP3474900A1 EP17816295.4A EP17816295A EP3474900A1 EP 3474900 A1 EP3474900 A1 EP 3474900A1 EP 17816295 A EP17816295 A EP 17816295A EP 3474900 A1 EP3474900 A1 EP 3474900A1
Authority
EP
European Patent Office
Prior art keywords
linker
degron
alkyl
formula
bifunctional compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP17816295.4A
Other languages
German (de)
English (en)
Other versions
EP3474900A4 (fr
Inventor
Dennis BUCKLEY
James Bradner
David Ian REMILLARD
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dana Farber Cancer Institute Inc
Original Assignee
Dana Farber Cancer Institute Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dana Farber Cancer Institute Inc filed Critical Dana Farber Cancer Institute Inc
Publication of EP3474900A1 publication Critical patent/EP3474900A1/fr
Publication of EP3474900A4 publication Critical patent/EP3474900A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/555—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
    • A61K47/556—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells enzyme catalyzed therapeutic agent [ECTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • UPP Ubiquitin-Proteasome Pathway
  • E3 ubiquitin ligases comprise over 500 different proteins and are categorized into multiple classes defined by the structural element of their E3 functional activity. For example, cereblon (CRBN) interacts with damaged DNA binding protein 1 and forms an E3 ubiquitin ligase complex with Cullin 4 in which the proteins recognized by CRBN are ubiquitinated and degraded by proteasomes.
  • immunomodulatory drugs e.g., thalidomide and lenalidomide
  • CRBN CRBN
  • thalidomide and lenalidomide binds to CRBN and modulates CRBN’s role in the ubiquitination and degradation of protein factors involved in maintaining regular cellular function.
  • Bifunctional compounds composed of a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety have been shown to induce proteasome-mediated degradation of selected proteins. These drug-like molecules offer the possibility of temporal control over protein expression, and could be useful as biochemical reagents for the treatment of diseases.
  • SWI/SNF or BAF nucleosome-remodeling complex is part of the SWI/SNF or BAF nucleosome-remodeling complex.
  • the SWI/SNF or BAF nucleosome-remodeling complex is a highly conserved multi-subunit complex, which uses the energy of ATP hydrolysis to remodel chromatin and mobilize nucleosomes.
  • SWI/SNF has also been shown to be required for transcriptional repression of some genes, suggesting that SWI/SNF controls transcription in diverse ways.
  • SWI/SNF possess intrinsic tumour-suppressor activity or are required for the activity of other tumour-suppressor genes, supporting a role of this complex in cancer development.
  • conditional inactivation of the Snf5 gene results in a highly penetrant cancer phenotype in mice.
  • genes encoding subunits of the SWI/SNF or BAF complex are mutated in cancer about 20% of the time.
  • the present application relates to novel bifunctional compounds, which function to recruit targeted proteins to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof.
  • the bifunctional com ound is of Formula X:
  • Targeting Ligand is capable of binding to a targeted protein, such as a
  • bromodomain-containing protein e.g., BRD9
  • the Linker is a group that covalently binds to the Targeting Ligand and the Degron;
  • the Degron is capable of binding to a ubiquitin ligase, such as an E3 ubiquitin ligase (e.g., cereblon).
  • a ubiquitin ligase such as an E3 ubiquitin ligase (e.g., cereblon).
  • the present application also relates to targeted degradation of proteins through the use of bifunctional compounds, including bifunctional compounds that link an E3 ubiquitin ligase-binding moiety to a ligand that binds the targeted proteins.
  • bifunctional compounds including bifunctional compounds that link an E3 ubiquitin ligase-binding moiety to a ligand that binds the targeted proteins.
  • R 1 , R 2 , A, and n are each as defined herein;
  • the Linker is a group that covalently binds to in Formula (I) and the Degron;
  • the Degron is capable of binding to a ubiquitin ligase, such as an E3 ubiquitin ligase (i.e., cereblon); and
  • Targeting Ligand is capable of binding to a targeted protein, such as BRD9.
  • the present application further relates to a Degron of Formula D1 or Formula D2:
  • Y, Z, Z 4 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , v, q, and q' are each as defined herein.
  • the present application further includes a Linker of Formula L1, L2, or L3:
  • the Linker is covalently bonded to a Degron via the next to Q, Q 2 , or Q 3 , and covalently bonded to a Targeting Ligand via the next to
  • the present application also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a bifunctional compound of the application, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.
  • Another aspect of the present application relates to a method of inhibiting a bromodomain protein (e.g., BRD9).
  • the method comprises administering to a subject in need thereof an effective amount of a bifunctional compound of the application, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition of the application.
  • Another aspect of the present application relates to a method of modulating (e.g., decreasing) the amount of a bromodomain protein (e.g., BRD9).
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of the application, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition of the application.
  • Another aspect of the present application relates to a method of inhibiting BRD9.
  • the method comprises administering to a subject in need thereof an effective amount of a bifunctional compound of the application, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition of the application.
  • Another aspect of the present application relates to a method of modulating BRD9.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of the application, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition of the application.
  • Another aspect of the present application relates to a method of treating or preventing a disease (e.g., a disease in which BRD9 plays a role).
  • the method comprises administering to a subject in need thereof an effective amount of a bifunctional compound of the application, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition of the application.
  • the disease is BRD9 mediated disorder.
  • the disease is a proliferative disease (e.g., a proliferative disease in which BRD9 plays a role).
  • Another aspect of the present application relates to a method of treating or preventing cancer in a subject, wherein the cancer cell comprises an activated BRD9 or wherein the subject is identified as being in need of BRD9 inhibition for the treatment or prevention of cancer.
  • the method comprises administering to the subject an effective amount of a bifunctional compound of the application, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition of the application.
  • kits comprising a bifunctional compound capable of inhibiting BRD9 activity, selected from a bifunctional compound of the application, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.
  • kits comprising a bifunctional compound capable of modulating (e.g., decreasing) the amount of BRD9, selected from a bifunctional compound of the application, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.
  • Another aspect of the present application relates to a bifunctional compound of the application, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition of the application, for use in the manufacture of a medicament for inhibiting a bromodomain protein (e.g., BRD9) or for modulating (e.g., decreasing) the amount of a bromodomain protein (e.g., BRD9).
  • a bromodomain protein e.g., BRD9
  • BRD9 bromodomain protein
  • Another aspect of the present application relates to a bifunctional compound of the application, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition of the application, for use in the manufacture of a medicament for inhibiting BRD9 or for modulating (e.g., decreasing) the amount of BRD9.
  • Another aspect of the present application relates to a bifunctional compound of the application, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition of the application, for use in the manufacture of a medicament for treating or preventing a disease (e.g., a disease in which BRD9 plays a role).
  • a disease e.g., a disease in which BRD9 plays a role
  • the disease is a BRD9 mediated disorder.
  • the disease is a proliferative disease (e.g., a proliferative disease in which BRD9 plays a role).
  • Another aspect of the present application relates to a bifunctional compound of the application, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition of the application, for use in the manufacture of a medicament for treating or preventing cancer in a subject, wherein the cancer cell comprises an activated BRD9 or wherein the subject is identified as being in need of BRD9 inhibition for the treatment or prevention of cancer.
  • Another aspect of the present application relates to a bifunctional compound of the application, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition of the application, for use in inhibiting a bromodomain protein (e.g., BRD9) or modulating (e.g., decreasing) the amount of a bromodomain protein (e.g., BRD9).
  • a bromodomain protein e.g., BRD9
  • modulating e.g., decreasing
  • Another aspect of the present application relates to a bifunctional compound of the application, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition of the application, for use in inhibiting BRD9 or modulating (e.g., decreasing) the amount of BRD9.
  • Another aspect of the present application relates to a bifunctional compound of the application, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition of the application, for use in treating or preventing a disease (e.g., a disease in which BRD9 plays a role).
  • a disease e.g., a disease in which BRD9 plays a role
  • the disease is BRD9 mediated disorder.
  • the disease is a proliferative disease (e.g., a proliferative disease in which BRD9 plays a role).
  • Another aspect of the present application relates to a bifunctional compound of the application, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition of the application, for use in treating or preventing cancer in a subject, wherein the cancer cell comprises an activated BRD9 or wherein the subject is identified as being in need of BRD9 inhibition for the treatment or prevention of cancer.
  • the present application provides inhibitors of BRD9 that are therapeutic agents in the treatment or prevention of diseases such as cancer and metastasis.
  • the present application further provides compounds and compositions with an improved efficacy and/or safety profile relative to known BRD9 inhibitors.
  • the present application also provides agents with novel mechanisms of action toward BRD9 proteins in the treatment of various types of diseases including cancer and metastasis.
  • the compounds and methods of the present application address unmet needs in the treatment of diseases or disorders in which pathogenic or oncogenic endogenous proteins (e.g., BRD9) play a role, such as cancer.
  • pathogenic or oncogenic endogenous proteins e.g., BRD9
  • FIG.1A is a graph measuring the formation of the BRD9:CRBN-DDBI protein complex induced by compound I-1 and unmodified thalidomide as detected by luminescence. The luminescence signal was measured as the concentration of compound I-1 and
  • thalidomide was decreased.
  • Compound I-1 was able to significantly induce formation of the complex relative to unmodified thalidomide.
  • the x-axis is compound concentration measured in log units and the y-axis is the alpha signal measured in intensity.
  • FIG.1B is a graph measuring the formation of the BRD9:CRBN-DDBI protein complex induced by compound I-2 and unmodified thalidomide as detected by luminescence.
  • the luminescence signal was measured as the concentration of compound I-2 and
  • thalidomide was decreased.
  • Compound I-2 was able to significantly induce formation of the complex relative to unmodified thalidomide.
  • the x-axis is compound concentration measured in log units and the y-axis is the alpha signal measured in intensity.
  • FIG.1C is a graph measuring the formation of the BRD9:CRBN-DDBI protein complex induced by compound I-3 and unmodified thalidomide as detected by luminescence.
  • the luminescence signal was measured as the concentration of compound I-3 and thalidomide was decreased.
  • Compound I-3 was able to significantly induce formation of the complex relative to unmodified thalidomide.
  • the x-axis is compound concentration measured in log units and the y-axis is the alpha signal measured in intensity.
  • FIG.2A is a graph measuring the formation of the BRD9:CRBN-DDBI protein complex induced by compound I-8 and unmodified thalidomide as detected by luminescence.
  • the luminescence signal was measured as the concentration of compound I-8 and thalidomide was decreased.
  • Compound I-8 was able to significantly induce formation of the complex relative to unmodified thalidomide.
  • the x-axis is compound concentration measured in log units and the y-axis is the alpha signal measured in intensity.
  • FIG.2B is a graph measuring the formation of the BRD9:CRBN-DDBI protein complex induced by compound I-7 and unmodified thalidomide as detected by luminescence.
  • the luminescence signal was measured as the concentration of compound I-7 and thalidomide was decreased.
  • Compound I-7 was able to significantly induce formation of the complex relative to unmodified thalidomide.
  • the x-axis is compound concentration measured in log units and the y-axis is the alpha signal measured in intensity.
  • FIG.2C is a graph measuring the formation of the BRD9:CRBN-DDBI protein complex induced by compound I-9 and unmodified thalidomide as detected by luminescence.
  • the luminescence signal was measured as the concentration of compound I-9 and thalidomide was decreased.
  • Compound I-9 was able to significantly induce formation of the complex relative to unmodified thalidomide.
  • the x-axis is compound concentration measured in log units and the y-axis is the alpha signal measured in intensity.
  • FIG.3A is a graph measuring the formation of the BRD9:CRBN-DDBI protein complex induced by compound I-5 and unmodified thalidomide as detected by luminescence.
  • the luminescence signal was measured as the concentration of compound I-5 and thalidomide was decreased.
  • Compound I-5 was able to significantly induce formation of the complex relative to unmodified thalidomide.
  • the x-axis is compound concentration measured in log units and the y-axis is the alpha signal measured in intensity.
  • FIG.3B is a graph measuring the formation of the BRD9:CRBN-DDBI protein complex induced by compound I-17 and un ied thalidomide as detected by luminescence.
  • the luminescence signal was measured as the concentration of compound I- 17 and thalidomide was decreased.
  • Compound I-17 was able to significantly induce formation of the complex relative to unmodified thalidomide.
  • the x-axis is compound concentration measured in log units and the y-axis is the alpha signal measured in intensity.
  • FIG.3C is a graph measuring the formation of the BRD9:CRBN-DDBI protein complex induced by compound I-12 and unmodified thalidomide as detected by luminescence.
  • the luminescence signal was measured as the concentration of compound I- 12 and thalidomide was decreased.
  • Compound I-12 was able to significantly induce formation of the complex relative to unmodified thalidomide.
  • the x-axis is compound concentration measured in log units and the y-axis is the alpha signal measured in intensity.
  • FIG.4A is a graph measuring the formation of the BRD9:CRBN-DDBI protein complex induced by compound I-15 and unmodified thalidomide as detected by luminescence.
  • the luminescence signal was measured as the concentration of compound I- 15 and thalidomide was decreased.
  • Compound I-15 was able to significantly induce formation of the complex relative to unmodified thalidomide.
  • the x-axis is compound concentration measured in log units and the y-axis is the alpha signal measured in intensity.
  • FIG.4B is a graph measuring the formation of the BRD9:CRBN-DDBI protein complex induced by compound I-24 and unmodified thalidomide as detected by luminescence.
  • the luminescence signal was measured as the concentration of compound I- 24 and thalidomide was decreased.
  • Compound I-24 was able to significantly induce formation of the complex relative to unmodified thalidomide.
  • the x-axis is compound concentration measured in log units and the y-axis is the alpha signal measured in intensity.
  • FIG.4C is a graph measuring the formation of the BRD9:CRBN-DDBI protein complex induced by compound I-25 and unmodified thalidomide as detected by luminescence.
  • the luminescence signal was measured as the concentration of compound I- 25 and thalidomide was decreased.
  • Compound I-25 was able to significantly induce formation of the complex relative to unmodified thalidomide.
  • the x-axis is compound concentration measured in log units and the y-axis is the alpha signal measured in intensity.
  • FIG.5A is a Western Blot image of the effect of 500, 50, and 10 nM of I-1 on BRD9 degradation where actin was used as a control.
  • FIG.5B is a Western Blot image of the effect of 500, 50, and 10 nM of I-2 on BRD9 degradation where actin was used as a control.
  • FIG.5C is a Western Blot image of the effect of 500, 50, and 10 nM of I-3 on BRD9 degradation where actin was used as a contr
  • FIG.5D is a Western Blot image of the effect of 500, 50, and 10 nM of I-8 on BRD9 degradation where actin was used as a control.
  • FIG.5E is a Western Blot image of the effect of 500, 50, and 10 nM of I-7 on BRD9 degradation where actin was used as a control.
  • FIG.5F is a Western Blot image of the effect of 500, 50, and 10 nM of I-13 on BRD9 degradation where actin was used as a control.
  • FIG.6A is a Western Blot image of the effect of 500, 50, and 10 nM of I-14 on BRD9 degradation where actin was used as a control.
  • FIG.6B is a Western Blot image of the effect of 500, 50, and 10 nM of I-9 on BRD9 degradation where actin was used as a control.
  • FIG.6C is a Western Blot image of the effect of 500, 50, and 10 nM of I-5 on BRD9 degradation.
  • FIG.6D is a Western Blot image of the effect of 500, 50, and 10 nM of I-17 on BRD9 degradation where actin was used as a control.
  • FIG.7A is a Western Blot image of the effect of 500, 50, and 10 nM of I-12 on BRD9 degradation where actin was used as a control.
  • FIG.7B is a Western Blot image of the effect of 500, 50, and 10 nM of I-15 on BRD9 degradation where actin was used as a control.
  • FIG.7C is a Western Blot image of the effect of 500, 50, and 10 nM of I-23 on BRD9 degradation where actin was used as a control.
  • FIG.7D is a Western Blot image of the effect of 500, 50, and 10 nM of I-24 on BRD9 degradation where actin was used as a control.
  • FIG.7E is a Western Blot image of the effect of 500, 50, and 10 nM of I-25 on BRD9 degradation where actin was used as a control.
  • FIG.8A is a high-resolution image showing compound I-8 overlaid with the crystal structure (PDB code 4UIV) of human BRD9 bromodomain with N-(1,1-dioxo-1-thian-4-yl)- 5-methyl-4- oxo-7-3-(trifluoromethyl)phenyl-4H,5H-thieno-3,2-c-pyridine-2- carboximidamide, a small molecule with a structure similar to the bromodomain targeting ligand portion of I-8.
  • the two compounds have significant overlap confirming that I-8 has a conserved binding mode relative to the free bromodomain targeting ligand with the derivatized methoxy position projected to solvent. Hydrogen bonding to the key Asp residue is highlighted.
  • FIG.8B is a dose-response curve comparing I-17 and I-25 in a BRD4-ligand displacement assay to determine selectivity st BRD4.
  • the small molecule JQ1, a BRD4 inhibitor was used as a control.
  • Compound I-25 which exhibited less activity at BRD4 than I-17, has increased selectivity against BRD4 compared to I-17.
  • the x-axis is the compound concentration measured in log units and the y-axis is the normalized alpha signal measured in intensity.
  • FIG.9A is a schematic representation of the degrader design based on the
  • compound’ s interaction with the CRBN protein and the BRD9 protein.
  • FIG.9B is a dose-response curve comparing I-1, I-2, and I-8 in a BRD9-ligand displacement assay to determine selectivity for BRD9.
  • the x-axis is the compound concentration measured in log units and the y-axis is the normalized alpha signal measured in intensity.
  • FIG.10A is a graph measuring the formation of the BRD9:CRBN-DDBI protein complex induced by compounds I-1, I-2, I-8, and unmodified thalidomide as detected by luminescence.
  • the luminescence signal was measured as the concentration of the compounds was decreased. All of the compounds were able to significantly induce formation of the complex relative to unmodified thalidomide.
  • the x-axis is compound concentration measured in log units and the y-axis is the alpha signal measured in intensity.
  • FIG.10B is an image of compound I-8 crystalized with the BRD9 protein.
  • FIG.11A is an in-silico model of the assembly of the CRBN-DDB1 and BRD9 ligand-binding domains induced by compound I-8.
  • the ternary assembly, including CRBN- DDB1 demonstrated the steric feasibility of ternary formation, with the two ligand-binding domains brought into close assembly by I-8.
  • the crystal structure of I-8 with BRD9 ( Figure 10B) was docked into the published structure of CRBN-DDB1.
  • FIG.11B are Western Blot images quantifying BRD9 and actin in a human AML-cell line (MOLM-13) by immunoblot after a 4 hour treatment with the indicated concentrations of compounds I-1, I-2, or I-8. Marked protein loss was observed at high concentrations of the potent dimerizers I-2 and I-8.
  • FIG.12A is a dose-response curve measuring the formation of the BRD9:CRBN- DDB1 complex induced by I-1, I-8, I-5, and I-17 compared to unmodified thalidomide as detected by luminescence.
  • the x-axis is compound concentration measured in log units and the y-axis is the normalized alpha signal measured in intensity.
  • FIG.12B are Western Blot images quantifying BRD9 and actin in a human AML-cell line (MOLM-13) by immunoblot after a 4 hour treatment with the indicated concentrations of compounds I-5 and I-17. Both compounds were able to effectively downregulate BRD9 over a broad range of concentrations.
  • FIG.13A is a Western Blog image quantifying BRD9 and actin in a human AML-cell line (MOLM-13) by immunoblot after 1, 2, 4, 16, and 24 hours with and without treatment of 100 nM of I-17 to assess the timecourse of degradation. Near complete BRD9 loss was observed within 1 hour of I-17 treatment, with no detectable return observed for the duration of the 24-hour treatment period. This profile is appropriate to enable study of primary consequences of acute BRD9 loss, as well as viability defects manifested over one or potentially more days.
  • FIG.13B is a Western Blot image quantifying BRD9 and actin in human multiple myeloma (MM1S) cells by immunoblot.
  • the cell lines were pretreated for 4 hours with vehicle (DMSO), I-BRD9 (a BRD9 inhibitor), lenalidomide, carfilzomib (a protease inhibitor), and MLN-4924 (a neddylation inhibitor) before exposure to 100 nM of I-17 to validate the cellular mechanism of I-17.
  • Pretreatment with excess I-BRD9 or lenalidomide competed with I-17 for binding to BRD9 or CRBN and prevented degradation, consistent with a requirement for intracellular engagement of both targets.
  • FIG.13C is a Western Blot image quantifying BRD9 and actin in MM1S WT cells and isogenic MMIS CRBN knockout cells (genetically edited by CRISP/Cas9) by immunoblot after a 4 hour treatment with the indicated doses of I-17 to establish a requirement of CRBN in degrading BRD9. While treatment of wild type MM.1S cells resulted in marked dose- dependent BRD9 loss, treatment of the MM.1S CRBNknockout cell line resulted in little to no BRD9 degradation, providing support for CRBN-dependent proteasomal degradation of BRD9 by I-17.
  • FIG.14A is a dendrogram of the human bromodomain family organized into eight subfamilies.
  • a single-point screen of I-17 at 32 members of the bromodomain family was conducted using BromoScan (experimental details are given in Example 6).
  • the circles with corresponding percentages represent the percentage of bromodomain isolated on the solid support compared to control during the BromoScan.
  • a control test without I-17 would result in 100% of broodomain on the solid support.
  • Compound I-17 not only interacts with BRD9 as represented in the dendrogram, but also BRD7 and members of the BET family.
  • FIG.14B are Western Blot images quantifying BRD9 and actin in a human AML-cell line (MOLM-13) by immunoblot after a 4 h eatment with the indicated concentrations of compound I-25. Compound I-25 induced BRD9 degradation over a broad range of concentrations.
  • FIG.15A is a dendrogram of the human bromodomain family organized into eight subfamilies.
  • a single-point screen of I-25 at 32 members of the bromodomain family was conducted using BromoScan (experimental details are given in Example 6).
  • the circles with corresponding percentages represent the percentage of bromodomain isolated on the solid support compared to control during the BromoScan.
  • a control test without I-25 would result in 100% of broodomain on the solid support.
  • Compound I-25 exclusively interacts with BRD9.
  • FIG.15B is a graph measuring the formation of the BRD9:CRBN-DDBI protein complex induced by compounds I-17, I-25, and unmodified pomalidomide as detected by luminescence.
  • the luminescence signal was measured as the concentration of the compounds was decreased.
  • Compounds I-17 and I-25 were able to significantly induce formation of the complex relative to unmodified pomalidomide.
  • the x-axis is compound concentration measured in log units and the y-axis is the alpha signal measured in intensity.
  • FIG.16A is a graph measuring the formation of the BRD4:CRBN-DDBI protein complex induced by compounds I-17, I-25, and unmodified pomalidomide as detected by luminescence. The luminescence signal was measured as the concentration of the compounds was decreased. Compound I-25 exhibited selectivity for BRD9 and induced no formation of the BRD4:CRBN-DDBI protein complex. The x-axis is compound
  • concentration measured in log units and the y-axis is the alpha signal measured in intensity.
  • FIG.16B are Western Blot images quantifying BRD4 and tubulin in a human AML- cell line (MOLM-13) by immunoblot after a 4 hour treatment with the indicated
  • FIG.17A are Western Blot images quantifying BRD7 and actin in a human AML-cell line (MOLM-13) by immunoblot after a 4 hour treatment with the indicated concentrations of compound I-17 and I-25.
  • Compound I-25 was not able to induce degradation of BRD7 at any of the concentrations, but degradation was observed for I-17.
  • FIG.17B is a dose-response curve of human AML (MOLM-13 cell line) cellular viability following 72 hour treatment with I-25 and I-17 compared to treatment with I-BRD9 and BI-7273, known BRD9 inhibitors.
  • the x-axis is compound concentration measured in log units and the y-axis is normalized luminescence measured in intensity.
  • FIG.18A is a dose-response curve of human AML (MV411 cell line) cellular viability following 72 hour treatment with I-25 and I-17 compared to treatment with I-BRD9 and BI-7273, known BRD9 inhibitors.
  • the x-axis is compound concentration measured in log units and the y-axis is normalized luminescence measured in intensity. Experimental details are given in Example 13.
  • FIG.18B is a dose-response curve of human multiple myeloma (MM1S) cellular viability following 72 hour treatment with I-25 and I-17 compared to treatment with I-BRD9 and BI-7273, known BRD9 inhibitors.
  • the x-axis is compound concentration measured in log units and the y-axis is normalized luminescence measured in intensity. Experimental details are given in Example 13.
  • FIG.19 is a dose-response curve of human multiple myeloma CRBN knockout (MM1S CRBN -/- ) cellular viability following 72 hour treatment with I-25 and I-17 compared to treatment with I-BRD9 and BI-7273, known BRD9 inhibitors.
  • the x-axis is compound concentration measured in log units and the y-axis is normalized luminescence measured in intensity. Experimental details are given in Example 13. DETAILED DESCRIPTION
  • the present application relates to novel bifunctional compounds, which function to recruit targeted proteins to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof.
  • the bifunctional com ound is of Formula X:
  • Targeting Ligand is capable of binding to a targeted protein, such as a bromodomain-containing protein (e.g., BRD9);
  • a targeted protein such as a bromodomain-containing protein (e.g., BRD9);
  • the Linker is a group that covalently binds to the Targeting Ligand and the Degron;
  • the Degron is capable of binding to a ubiquitin ligase, such as an E3 ubiquitin ligase (e.g., cereblon).
  • a ubiquitin ligase such as an E3 ubiquitin ligase (e.g., cereblon).
  • the present application also relates to targeted degradation of proteins through the use of bifunctional compounds, including bifunctional compounds that link an E3 ubiquitin ligase-binding moiety to a ligand that binds the targeted proteins.
  • the present application also relates to a bifunctional compound of Formula I:
  • R 1 , R 2 , A, and n are each as defined herein;
  • the Linker is a group that covalently binds to in Formula (I) and the Degron;
  • the Degron is capable of binding to a ubiquitin ligase, such as an E3 ubiquitin ligase (i.e., cereblon); and
  • Targeting Ligand is capable of binding to a targeted protein, such as BRD9.
  • the present application further relates to a Degron of Formula D1:
  • the present application further relates to a Degron of Formula D2:
  • the present application further relates to a Linker of Formula L1:
  • the Linker is covalently bonded to a Degron via the next to Q, and covalently bonded to a Targeting Ligand via the next to Z 1 .
  • the present application further relates to a Linker of Formula L2:
  • the Linker is covalently bonded to a Degron via the next to Q 2 , and covalently bonded to the Targeting Ligand via the next to Z2.
  • the present application further relates to a Linker of Formula L3:
  • the Linker is covalently bonded to a Degron via the next to Q 3 , and covalently bonded to a Targeting Ligand via the next to Z 3 .
  • Targeting Ligand (or target protein moiety or target protein ligand or ligand) is a small molecule which is capable of binding to a target protein of interest, such BRD9.
  • a Targeting Ligand is a compound of Formula TL-I:
  • A is phenyl or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S, wherein the phenyl or heteroaryl is optionally substituted with 1 to 3 R 3 ;
  • R 1 is H, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) haloalkyl;
  • each R 2 is independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, OH, or NH 2 ;
  • each R 3 is independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 )
  • haloalkoxy halogen, OH, NH 2 , or
  • X 1 is NR 5 or O
  • Y 1 is S(O) a or NR 5 ;
  • each R 4 is independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, halogen, or -C(O)(C 1 - C 3 )alkyl;
  • each R 5 is independently H or (C 1 -C 4 ) alkyl
  • R 6 is H or (C 1 -C 4 ) alkyl
  • a 0, 1, or 2;
  • n and r are each independently 0, 1, 2, or 3; wherein the Targeting Ligand is bonded to the Linker via the next to
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • each A is optionally substituted with 1 to 3 R 3 .
  • A is or , wherein each A is optionally substituted with 1 to 3
  • A is, , , , or , wherein
  • each A is optionally substituted with 1 to 3 R3. In other embodiments, A is
  • A is optionally substituted with 1 to 3 R 3 .
  • A is optionally substituted with 1 to 3 R 3 .
  • N substituted with 1 to 3 R3.
  • A is optionally substituted with
  • A is optionally substituted with 1 to 3 R3.
  • N is optionally substituted with 1 to 3 R3.
  • A is optionally substituted with 1 to 3 R 3 .
  • A is , wherein each A is optionally substituted with 1 to
  • A is optionally substituted with 1 to 3 R 3 . In other embodiments, A is optionally substituted with 1 to 3 R 3 . In other
  • A is optionally substituted with 1 to 3 R 3 . In other embodiments, A is .
  • R 1 is H, (C 1 -C 3 ) alkyl, or (C 1 -C 3 ) haloalkyl. In other embodiments, R 1 is H or (C 1 -C 4 ) alkyl. In other embodiments, R 1 is H, methyl, ethyl, n- propyl, or i-propyl. In other embodiments, R 1 is H, methyl or ethyl. In other embodiments, R 1 is H. In other embodiments, R 1 is (C 1 -C 4 ) alkyl. In other embodiments, R 1 is methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R 1 is methyl or ethyl. In other embodiments, R 1 is (C 1 -C 4 ) alkyl or (C 1 -C 4 ) haloalkyl.
  • At least one R 2 is (C 1 -C 3 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 3 ) alkoxy, (C1-C3) haloalkoxy, halogen, OH, or NH2.
  • at least one R2 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, or halogen.
  • at least one R2 is halogen, OH, or NH2.
  • At least one R2 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, or (C 1 -C 4 ) haloalkoxy.
  • at least one R 2 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, or halogen.
  • at least one R 2 is (C 1 -C 4 ) alkoxy or halogen.
  • at least one R 2 is (C 1 -C 4 ) alkoxy.
  • at least one R 2 is (C 1 -C 3 ) alkoxy.
  • At least one R 2 is methoxy, ethoxy, n-propoxy, or i-propoxy. In other embodiments, at least one R 2 is methoxy or ethoxy. In other embodiments, at least one R 2 is methoxy.
  • At least one R 3 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 )
  • At least one R 3 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkox halo en OH, or NH 2 . In some embodiments, at least one R 3 is In other embodiments, at least one R 3 is (C 1 -C 4 ) alkyl, (C 1 -C 4 )
  • haloalkyl (C 1 -C 4 ) alkoxy, or (C 1 -C 4 ) haloalkoxy.
  • at least one R 3 is (C 1 -C 4 ) alkyl, halogen, OH, or NH 2 .
  • at least one R 3 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, halogen, OH, or NH 2 .
  • At least one R 3 is (C 1 -C 3 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) haloalkoxy, halogen, OH, or NH 2 .
  • X 1 is NR 5 . In other embodiments, X 1 is NH. In other embodiments, X 1 is O.
  • Y1 is S(O)a. In other embodiments, Y1 is S(O)2. In other embodiments, Y 1 is S(O). In other embodiments, Y 1 is S. In other embodiments, Y 1 is NR 5 .
  • At least one R4 is (C1-C3) alkyl, (C1-C3) haloalkyl, halogen, or - C(O)(C 1 -C 3 )alkyl. In other embodiments, at least one R 4 is (C 1 -C 3 ) alkyl, (C 1 -C 3 ) haloalkyl, or halogen. In other embodiments, at least o 4 is (C 1 -C 3 ) alkyl, (C 1 -C 3 ) haloalkyl, or - C(O)(C 1 -C 3 )alkyl.
  • At least one R 4 is (C 1 -C 3 ) alkyl, halogen, or - C(O)(C 1 -C 3 )alkyl. In other embodiments, at least one R 4 is (C 1 -C 3 ) alkyl or -C(O)(C 1 - C 3 )alkyl. In other embodiments, at least one R 4 is (C 1 -C 3 ) alkyl or halogen.
  • R 5 is H or (C 1 -C 3 ) alkyl. In other embodiments, R 5 is H. In other embodiments, R5 is (C1-C4) alkyl. In other embodiments, R5 is (C1-C3) alkyl. In other embodiments, R 5 is H, methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R 5 is H, methyl, or ethyl. In other embodiments, R5 is methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R 5 is methyl or ethyl.
  • R 6 is H or (C 1 -C 3 ) alkyl. In other embodiments, R 6 is H. In other embodiments, R 6 is (C 1 -C 4 ) alkyl. In other embodiments, R 6 is (C 1 -C 3 ) alkyl. In other embodiments, R 6 is H, methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R 6 is H, methyl, or ethyl. In other embodiments, R 6 is methyl, ethyl, n-propyl, or i-propyl. In other embodiments, R 6 is methyl or ethyl.
  • a is 0. In other embodiments, a is 1. In other embodiments, a is 2. In other embodiments, a is 0 or 1. In other embodiments, a is 1 or 2.
  • n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3. In other embodiments, n is 0 or 1. In other embodiments, n is 1 or 2. In other embodiments, n is 0, 1 or 2. In other embodiments, n is 1, 2 or 3.
  • r is 0. In other embodiments, r is 1. In other embodiments, r is 2. In other embodiments, r is 3. In other embodiments, r is 0 or 1. In other embodiments, r is 1 or 2. In other embodiments, r is 0, 1 or 2. In other embodiments, r is 1, 2 or 3.
  • any of the groups described herein for any of A, X 1 , Y 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , a, n, and r can be combined with any of the groups described herein for one or more of the remainder of A, X1, Y1, R1, R2, R3, R4, R5, R6, a, n, and r, and may further be combined with any of the groups described herein for the Linker.
  • A is and R 3 is 6
  • A is R 3 is , and X 1 is NR 5 .
  • A is and X 1 is NH.
  • A is and X 1 is O.
  • A is and Y 1 is S.
  • A is and Y 1 is S(O).
  • A is and Y 1 is S(O)2.
  • A is X 1 is NR 5 , and Y1 is S.
  • A is X 1 is NR 5 , and Y 1 is S(O).
  • A is X 1 is NR 5 , and Y 1 is S(O) 2 .
  • A is X 1 is NH, and Y 1 is S.
  • A is X 1 is NH, and Y 1 is S(O).
  • A is X 1 is NH, and Y 1 is S(O) 2 .
  • A is X 1 is O, and Y 1 is S.
  • A is X1 is O, and Y 1 is S(O).
  • A is X 1 is O, and Y 1 is S(O) 2 .
  • A, R 3 , X 1 , and Y 1 are each as defined, where applicable, in any one of (1)-(16), and R 1 is H.
  • A, R 3 , X 1 , and Y 1 are each as defined, where applicable, in any one of (1)-(16), and R 1 is (C 1 -C 4 ) alkyl.
  • A, R 3 , X 1 , and Y 1 are each as defined, where applicable, in any one of (1)-(16), and R 1 is methyl.
  • A, R 3 , X 1 , and Y 1 are each as defined, where applicable, in any one of (1)-(16), and R 1 is ethyl.
  • A, R 3 , X 1 , and Y 1 are each as defined, where applicable, in any one of (1)-(16), and R 2 is (C 1 -C 4 ) alkoxy.
  • A, R 3 , X 1 , and Y 1 are each as defined, where applicable, in any one of (1)-(16), and R 2 is (C 1 -C 4 ) methoxy.
  • A, R 3 , X 1 , and Y 1 are each as defined, where applicable, in any one of (1)-(16), R 1 is H, and R C 1 -C 4 ) alkoxy.
  • A, R 3 , X 1 , and Y 1 are each as defined, where applicable, in any one of (1)-(16), R 1 is H, and R 2 is (C 1 -C 4 ) methoxy.
  • A, R 3 , X 1 , and Y 1 are each as defined, where applicable, in any one of (1)-(16), R 1 is (C 1 -C 4 ) alkyl, and R 2 is (C 1 -C 4 ) alkoxy.
  • A, R3, X1, and Y1 are each as defined, where applicable, in any one of (1)-(16), R 1 is (C 1 -C 4 ) alkyl, and R 2 is methoxy.
  • A, R3, X1, and Y1 are each as defined, where applicable, in any one of (1)-(16), R 1 is methyl, and R 2 is (C 1 -C 4 ) alkoxy.
  • A, R 3 , X 1 , and Y 1 are each as defined, where applicable, in any one of (1)-(16), R 1 is methyl, and R 2 is methoxy.
  • A, R 3 , X 1 , and Y 1 are each as defined, where applicable, in any one of (1)-(16), R 1 is ethyl, and R 2 is (C 1 -C 4 ) alkoxy.
  • A, R 3 , X 1 , and Y 1 are each as defined, where applicable, in any one of (1)-(16), R 1 is ethyl, and R 2 is methoxy.
  • A, R 1 , R 3 , X 1 , and Y 1 are each as defined in any one of (17)-(20), and n is 1.
  • A, R 1 , R 3 , X 1 , and Y 1 are each as defined in any one of (17)-(20), and n is 2.
  • A, R 2 , R 3 , X 1 , and Y 1 are each as defined in (21) or (22), and n is 1.
  • A, R 2 , R 3 , X 1 , and Y 1 are each as defined in (21) or (22), and n is 2.
  • A, R 1 , R 2 , R 3 , X 1 , and Y 1 are each as defined in any one of (23)-(30), and n is 1.
  • A, R 1 , R 2 , R 3 , X 1 , and Y 1 are each as defined in any one of (23)-(30), and n is 2.
  • A, R 1 , R 2 , R 3 , X 1 , Y 1 , and n are each as defined, where applicable, in any one of (31)-(36), and r is 0.
  • A, R 1 , R 2 , R 3 , X 1 , Y 1 , n, and r are each as defined, where applicable, in any one of (31)-(37), and R 6 is H.
  • A, R 1 , R 2 , R 3 , X 1 , Y 1 , n, and r are each as defined, where applicable, in any one of (31)-(37), and R 6 is methyl.
  • R 6 is methyl.
  • A is and R 1 is (C 1 -C 4 ) alkyl.
  • A is , R 1 is (C 1 -C 4 ) alkyl, and R 2 is (C 1 -C 4 ) alkoxy.
  • A is , R 1 is (C 1 -C 4 ) alkyl, and R 2 is methoxy.
  • A is and R1 ismethyl.
  • A is , R 1 is methyl, and R 2 is (C 1 -C 4 ) alkoxy.
  • A is , R 1 is methyl, and R 2 is methoxy.
  • A is and R 1 is ethyl.
  • A is , R 1 is ethyl, and R 2 is (C 1 -C 4 ) alkoxy.
  • A is , R 1 is ethyl, and R 2 is methoxy.
  • A is and R 1 is H.
  • A is , R 1 is H, and R 2 is (C 1 -C 4 ) alkoxy.
  • A is , R 1 is H, and R 2 is methoxy.
  • A, R 1 , and R 3 are each as defined, where applicable, in any one of (40)-(51), and n is 1.
  • A, R 1 , and R 3 are each as defined, where applicable, in any one of (40)-(51), and n is 2.
  • R1 is (C1-C4) alkyl and R2 is (C1-C4) alkoxy.
  • R 1 is (C 1 -C 3 ) alkyl and R 2 is (C 1 -C 3 ) alkoxy.
  • R1 is (C1-C4) alkyl and R2 is methoxy.
  • R 1 is methyl and R 2 is (C 1 -C 4 ) alkoxy.
  • R 1 is ethyl and R 2 is (C 1 -C 4 ) alkoxy.
  • R 1 is methyl and R 2 is methoxy.
  • R 1 is ethyl and R 2 is methoxy.
  • R 1 is (C 1 -C 4 ) alkyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 1.
  • R 1 is (C 1 -C 3 ) alkyl
  • R 2 is (C 1 -C 3 ) alkoxy
  • n is 1.
  • R 1 is (C 1 -C 4 ) alkyl
  • R 2 is methoxy
  • n is 1.
  • R 1 is methyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 1.
  • R 1 is ethyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 1.
  • R 1 is methyl
  • R 2 is methoxy
  • n is 1.
  • R 1 is ethyl
  • R 2 is methoxy
  • n is 1.
  • R 1 is (C 1 -C 4 ) alkyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 2.
  • R 1 is (C 1 -C 3 ) alkyl
  • R 2 is (C 1 -C 3 ) alkoxy
  • n is 2.
  • R 1 is (C 1 -C 4 ) alkyl
  • R 2 is methoxy
  • n is 2.
  • R 1 is methyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 2.
  • R 1 is ethyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 2.
  • R1 is methyl
  • R2 is methoxy
  • n is 2.
  • R 1 is ethyl
  • R 2 is methoxy
  • n is 2.
  • X 1 , Y 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , a, n, and r are each as defined above in Formula TL-I.
  • R 1 is (C 1 -C 4 ) alkyl and R 2 is (C 1 -C 4 ) alkoxy.
  • R 1 is (C 1 -C 3 ) alkyl and R 2 is (C 1 -C 3 ) alkoxy.
  • R 1 is (C 1 -C 4 ) alkyl and R 2 is methoxy.
  • R 1 is methyl and R 2 is (C 1 -C 4 ) alkoxy.
  • R1 is ethyl and R2 is (C1-C4) alkoxy.
  • R 1 is methyl and R 2 is methoxy.
  • R1 is ethyl and R2 is methoxy.
  • R 1 is (C 1 -C 4 ) alkyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 1.
  • R 1 is (C 1 -C 3 ) alkyl
  • R 2 is (C 1 -C 3 ) alkoxy
  • n is 1.
  • R 1 is (C 1 -C 4 ) alkyl
  • R 2 is methoxy
  • n is 1.
  • R 1 is methyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 1.
  • R 1 is ethyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 1.
  • R 1 is methyl
  • R 2 is methoxy
  • n is 1.
  • R 1 is ethyl
  • R 2 is methoxy
  • n is 1.
  • R 1 is (C 1 -C 4 ) alkyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 2.
  • R 1 is (C 1 -C 3 ) alkyl
  • R 2 is (C 1 -C 3 ) alkoxy
  • n is 2.
  • R 1 is (C 1 -C 4 ) alkyl
  • R 2 is methoxy
  • n is 2.
  • R 1 is methyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 2.
  • R 1 is ethyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 2.
  • R 1 is methyl
  • R 2 is methoxy
  • n is 2.
  • R 1 is ethyl
  • R 2 is methoxy
  • n is 2.
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), and X 1 is NR 5 .
  • R1, R2, and n are each as defined, where applicable, in any one of (1)-(21), and X 1 is NH.
  • R1, R2, and n are each as defined, where applicable, in any one of (1)-(21), X 1 is O.
  • R1, R2, and n are each as defined, where applicable, in any one of (1)-(21), and Y 1 is S.
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), and Y 1 is S(O).
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), and Y 1 is S(O) 2 .
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), X 1 is NR 5 , and Y 1 is S.
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), X 1 is NR 5 , and Y 1 is S(O).
  • R1, R2, and n are each as defined, where applicable, in any one of (1)-(21), X 1 is NR 5 , and Y 1 is S(O) 2 .
  • R1, R2, and n are each as defined, where applicable, in any one of (1)-(21), X 1 is NH, and Y 1 is S.
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), X 1 is NH, and Y 1 is S(O).
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), X 1 is NH, and Y 1 is S(O) 2 .
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), X 1 is O, and Y 1 is S.
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), X 1 is O, and Y 1 is S(O).
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), X 1 is O, and Y 1 is S(O) 2 .
  • X 1 is NR 5 and Y 1 is S(O) 2 .
  • X 1 is NH and Y 1 is S(O) 2 .
  • X 1 is O and Y 1 is S(O) 2 .
  • X 1 and Y 1 are each as defined in any one of (37)-(39), and r is 0.
  • X1 and Y1 are each as defined in any one of (37)-(39), and r is 1.
  • X1 and Y1 are each as defined in any one of (37)-(39), and r is 2.
  • X1, Y1, and r are each as defined, where applicable, in any one of (37)-(42), and R 1 is (C 1 -C 4 ) alkyl.
  • X 1 , Y 1 , and r are each as defined, where applicable, in any one of (37)-(42), and R 1 is methyl.
  • X 1 , Y 1 , and r are each as defined, where applicable, in any one of (37)-(42), and R 1 is ethyl.
  • R 1 is ethyl.
  • X 1 , Y 1 , and r are each as defined, where applicable, in any one of (37)-(42), and R 2 is (C 1 -C 4 ) alkoxy.
  • X 1 , Y 1 , and r are each as defined, where applicable, in any one of (37)-(42), and R 2 is (C 1 -C 4 ) ethoxy.
  • X1, Y1, R1, R2, and r are each as defined, where applicable, in any one of (37)-(47), and n is 1.
  • X1, Y1, R1, R2, and r are each as defined, where applicable, in any one of (37)-(47), and n is 2.
  • X 1 , Y 1 , R 1 , R 2 , R 4 , R 5 , R 6 , a, n, and r can each be selected from any of the groups and combined as described above in Formula TL-I.
  • X 1 , Y 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , a, n, and r are each as defined above in Formula TL-I.
  • R 1 is (C 1 -C 4 ) alkyl and R 2 is (C 1 -C 4 ) alkoxy.
  • R 1 is (C 1 -C 3 ) alkyl and R 2 is (C 1 -C 3 ) alkoxy.
  • R 1 is (C 1 -C 4 ) alkyl and R 2 is methoxy.
  • R 1 is methyl and R 2 is (C 1 -C 4 ) alkoxy.
  • R 1 is ethyl and R 2 is (C 1 -C 4 ) alkoxy.
  • R 1 is methyl and R 2 is methoxy.
  • R 1 is ethyl and R 2 is methoxy.
  • R 1 is (C 1 -C 4 ) alkyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 1.
  • R 1 is (C 1 -C 3 ) alkyl
  • R 2 is (C 1 -C 3 ) alkoxy
  • n is 1.
  • R 1 is (C 1 -C 4 ) alkyl
  • R 2 is methoxy
  • n is 1.
  • R 1 is methyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 1.
  • R 1 is ethyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 1.
  • R 1 is methyl
  • R 2 is methoxy
  • n is 1.
  • R 1 is ethyl
  • R 2 is methoxy
  • n is 1.
  • R 1 is (C 1 -C 4 ) alkyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 2.
  • R 1 is (C 1 -C 3 ) alkyl
  • R 2 is (C 1 -C 3 ) alkoxy
  • n is 2.
  • R 1 is (C 1 -C 4 ) alkyl
  • R 2 is methoxy
  • n is 2.
  • R 1 is methyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 2.
  • R 1 is ethyl
  • R 2 is (C 1 -C 4 ) alkoxy
  • n is 2.
  • R1 is methyl
  • R2 is methoxy
  • n is 2.
  • R 1 is ethyl
  • R 2 is methoxy
  • n is 2.
  • R1, R2, and n are each as defined, where applicable, in any one of (1)-(21), and X 1 is NR 5 .
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), and X 1 is NH.
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), X 1 is O.
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), and Y 1 is S.
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), and Y 1 is S(O).
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), and Y 1 is S(O) 2 .
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), X 1 is NR 5 , and Y 1 is S.
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), X 1 is NR 5 , and Y 1 is S(O).
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), X1 is NR5, and Y1 is S(O)2.
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), X1 is NH, and Y1 is S.
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), X1 is NH, and Y1 is S(O).
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), X 1 is NH, and Y 1 is S(O) 2 .
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), X 1 is O, and Y 1 is S.
  • R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), X 1 is nd Y 1 is S(O). (36) In one embodiment, R 1 , R 2 , and n are each as defined, where applicable, in any one of (1)-(21), X 1 is O, and Y 1 is S(O) 2 .
  • X 1 is NR 5 and Y 1 is S(O) 2 .
  • X 1 is NH and Y 1 is S(O) 2 .
  • X1 is O and Y1 is S(O)2.
  • X 1 and Y 1 are each as defined in any one of (37)-(39), and r is 0.
  • X 1 and Y 1 are each as defined in any one of (37)-(39), and r is 1.
  • X 1 and Y 1 are each as defined in any one of (37)-(39), and r is 2.
  • X 1 , Y 1 , and r are each as defined, where applicable, in any one of (37)-(42), and R 1 is (C 1 -C 4 ) alkyl.
  • X 1 , Y 1 , and r are each as defined, where applicable, in any one of (37)-(42), and R 1 is methyl.
  • X 1 , Y 1 , and r are each as defined, where applicable, in any one of (37)-(42), and R 1 is ethyl.
  • X 1 , Y 1 , and r are each as defined, where applicable, in any one of (37)-(42), and R 2 is (C 1 -C 4 ) alkoxy.
  • X 1 , Y 1 , and r are each as defined, where applicable, in any one of (37)-(42), and R 2 is (C 1 -C 4 ) ethoxy.
  • X 1 , Y 1 , R 1 , R 2 , and r are each as defined, where
  • X1, Y1, R1, R2, and r are each as defined, where
  • n is 2.
  • X1, Y1, R1, R2, R4, R5, R6, a, n, and r can each be selected from any of the groups and combined as described above in Formula TL-I.
  • T Targeting Ligand having the one of structures in Table A:
  • the Degron serves to link a targeted protein, through a Linker and a Targeting Ligand, to a ubiquitin ligase for proteosomal degradation.
  • the Degron is capable of binding to a ubiquitin ligase, such as an E3 ubiquitin ligase.
  • the Degron is capable of binding to cereblon.
  • the Degron is of Formula D1:
  • Y is a bond, (CH 2 ) 1-6 , (CH 2 ) 0-6 -O, (CH 2 ) 0-6 -C(O)NR 11 , (CH 2 ) 0-6 -NR 11 C(O), (CH 2 ) 0-6 -
  • R 11 is H or C 1 -C 6 alkyl
  • R 12 is C 1 -C 6 alkyl or C(O)-C 1 -C 6 alkyl
  • R 15 is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • each R 16 is independently halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • q 0, 1, or 2;
  • v is 0, 1, 2, or 3, wherein the Degron is covalently bonded to the Linker via .
  • Z is C(O).
  • Z is C(O) or CH 2 .
  • Z is C(R 13 ) 2 ; and each R 13 is H. In one embodiment, Z is C(R 13 ) 2 ; and one of R 13 is H, and the other is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl. In one embodiment, Z is C(R 13 ) 2 ; and each R 13 is independently selected from methyl, ethyl, and propyl.
  • Y is a bond
  • Y is a bond, O, or NH.
  • Y is (CH 2 ) 1 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 , (CH 2 ) 5 , or (CH 2 ) 6 .
  • Y is (CH2)1, (CH2)2, or (CH2)3.
  • Y is (CH2)1 or (CH2)2.
  • Y is O, CH 2 -O, (CH 2 ) 2 -O, (CH 2 ) 3 -O, (CH 2 ) 4 -O, (CH 2 ) 5 -O, or (CH 2 ) 6 -O.
  • Y is O, CH 2 -O, (CH 2 ) 2 -O, or (CH 2 ) 3 -O.
  • Y is O or CH 2 -O.
  • Y is O.
  • Y is C(O)NR 11 , CH 2 -C(O)NR 11 , (CH 2 ) 2 -C(O)NR 11 , (CH 2 ) 3 - C(O)NR 11 , (CH 2 ) 4 -C(O)NR 11 , (CH 2 ) 5 -C(O)NR 11 , or (CH 2 ) 6 -C(O)NR 11 .
  • Y is C(O)NR 11 , CH 2 -C(O)NR 11 , (CH 2 ) 2 -C(O)NR 11 , or (CH 2 ) 3 -C(O)NR 11 .
  • Y is C(O)NR 11 or CH 2 -C(O)NR 11 .
  • Y is C(O)NR 11 .
  • Y is NR 11 C(O), CH 2 -NR 11 C(O), (CH 2 ) 2 -NR 11 C(O), (CH 2 ) 3 - NR 11 C(O), (CH 2 ) 4 -NR 11 C(O), (CH 2 ) 5 -NR 11 C(O), or (CH 2 ) 6 -NR 11 C(O).
  • Y is NR 11 C(O), CH 2 -NR 11 C(O), (CH 2 ) 2 -NR 11 C(O), or (CH 2 ) 3 -NR 11 C(O).
  • Y is NR 11 C(O) or CH 2 -NR 11 C(O).
  • Y is NR 11 C(O).
  • R 11 is H. In one embodiment, R 11 is selected from methyl, ethyl, propyl, butyl, i-butyl, t-butyl, pentyl, i-pentyl, and hexyl. In one embodiment, R 11 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl.
  • Y is NH, CH 2 -NH, (CH 2 ) 2 -NH, (CH 2 ) 3 -NH, (CH 2 ) 4 -NH, (CH 2 ) 5 - NH, or (CH 2 ) 6 -NH.
  • Y is NH, CH 2 -NH, (CH 2 ) 2 -NH, or (CH 2 ) 3 -NH.
  • Y is NH or CH 2 -NH.
  • Y is NH.
  • Y is NR 12 , CH 2 -NR 12 , (CH 2 ) 2 -NR 12 , (CH 2 ) 3 -NR 12 , (CH 2 ) 4 -NR 12 , (CH 2 ) 5 -NR 12 , or (CH 2 ) 6 -NR 12 .
  • Y is NR 12 , CH 2 -NR 12 , (CH 2 ) 2 -NR 12 , or (CH 2 ) 3 -NR 12 .
  • Y is NR 12 or CH 2 -NR 12 .
  • Y is NR 12 .
  • R 12 is selected from methyl, ethyl, propyl, butyl, i-butyl, t-butyl, pentyl, i-pentyl, and hexyl. In one embodiment, R12 is C1-C3 alkyl selected from methyl, ethyl, and propyl.
  • R12 is selected from C(O)-methyl, C(O)-ethyl, C(O)-propyl, C(O)-butyl, C(O)-i-butyl, C(O)-t-butyl, C(O)-pentyl, C(O)-i-pentyl, and C(O)-hexyl.
  • R 12 is C(O)-C 1 -C 3 alkyl selected from C(O)-methyl, C(O)-ethyl, and C(O)- propyl.
  • R 13 is H.
  • R 13 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl. In one embodiment, R 13 is methyl.
  • q is 0.
  • q is 1.
  • q is 2.
  • each R 14 is independently C 1 -C 3 alkyl selected from methyl, ethyl, and propyl.
  • v is 0.
  • v is 1.
  • v is 2.
  • v is 3.
  • each R 16 is independently selected from halogen (e.g., F, Cl, Br, and I), OH, C1-C6 alkyl (e.g., methyl, ethyl, propyl, butyl, i-butyl, t-butyl, pentyl, i-pentyl, and hexyl), and C 1 -C 6 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, i-butoxy, t-butoxy, and pentoxy).
  • each R16 is independently selected from F, Cl, OH, methyl, ethyl, propyl, butyl, i-butyl, t-butyl, methoxy, and ethoxy.
  • R15 is H, deuterium, or C1-C3 alkyl. In another embodiment, R15 is H or C 1 -C 3 alkyl. In a further embodiment, R 15 is in the (S) or (R) configuration. In a further embodiment, R 15 is in the (S) configuration. In one embodiment, the compound comprises a racemic mixture of (S)-R 15 and (R)-R 15 .
  • R 15 is H.
  • R 15 is deuterium. In one embodiment, R 15 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl. In one embodiment, R 15 is methyl.
  • R 15 is F or Cl. In a further embodiment, R 15 is in the (S) or (R) configuration. In a further embodiment, R 15 is in the (R) configuration. In one embodiment, the compound comprises a racemic mixture of (S)-R15 and (R)-R15. In one embodiment, R15 is F.
  • any of the groups described herein for any of Y, Z, R11, R12, R13, R14, R15, R16, q and v can be combined with any of the groups described herein for one or more of the remainder of Y, Z, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , q and v, and may further be combined with any of the groups described herein for the Linker.
  • Z is C(O) and Y is a bond.
  • Z is C(O) and Y is NH.
  • Z is C(O) and Y is (CH 2 ) 0-6 -O. In a further embodiment, Y is O.
  • Z is C(O); Y is a bond; and q and v are each 0.
  • Z is C(O); Y is NH; and q and v are each 0.
  • Z is C(O); Y is (CH 2 ) 0-6 -O; and q and v are each 0. In a further embodiment, Y is O.
  • Z is C(O); Y is a bond; and R 13 is H.
  • Z is C(O); Y is a bond; and R 15 is H.
  • Z is C(O); Y is NH; and R 13 is H.
  • Z is C(O); Y is NH; and R 15 is H.
  • Z is C(O); Y is a bond; R13 is H; and R15 is H.
  • Z is C(O); Y is NH; R 13 is H; and R 15 is H.
  • Z is C(O); Y is (CH2)0-6-O; and R13 is H. In a further embodiment, Y is O.
  • Z is C(O); Y is (CH2)0-6-O; and R15 is H. In a further embodiment, Y is O.
  • Z is C(O); Y is (CH 2 ) 0-6 -O; R 13 is H; and R 15 is H. In a further embodiment, Y is O.
  • q and v are each 0; and Y, Z, R 13 , R 15 , and R 16 are each as defined in any of (1)– (3) and (7)– (15).
  • Z is CH Y is a bond.
  • Z is CH 2 and Y is NH.
  • Z is CH 2 and Y is (CH 2 ) 0-6 -O. In a further embodiment, Y is O.
  • Z is CH 2 ; Y is a bond; and q and v are each 0.
  • Z is CH2; Y is NH; and q and v are each 0.
  • Z is CH 2 ; Y is (CH 2 ) 0-6 -O; and q and v are each 0. In a further embodiment, Y is O.
  • Z is CH 2 ; Y is a bond; and R 13 is H.
  • Z is CH 2 ; Y is a bond; and R 15 is H.
  • Z is CH 2 ; Y is NH; and R 13 is H.
  • Z is CH 2 ; Y is NH; and R 15 is H.
  • Z is CH 2 ; Y is a bond; R 13 is H; and R 15 is H.
  • Z is CH 2 ; Y is NH; R 13 is H; and R 15 is H.
  • Z is CH 2 ; Y is (CH 2 ) 0-6 -O; and R 13 is H. In a further embodiment, Y is O.
  • Z is CH 2 ; Y is (CH 2 ) 0-6 -O; and R 15 is H. In a further embodiment, Y is O.
  • Z is CH 2 ; Y is (CH 2 ) 0-6 -O; R 13 is H; and R 15 is H. In a further embodiment, Y is O.
  • q and v are each 0; and Y, Z, R 13 , R 15 , and R 16 are each as defined in any of (17)– (19) and (23)– (31).
  • the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l:
  • Y is a bond, O, or NH. In one embodiment, Y is a bond. In one embodiment, Y is O. In one embodiment, Y is NH.
  • the Degron is of Formula D2:
  • Z4 is absent or C(O);
  • each R 17 is independently C 1 -C 3 alkyl
  • q' is 0, 1, 2, 3 or 4;
  • R 18 is H or C 1 -C 3 alkyl, he Degron is covalently bonded to another moiety (e.g., a compound, or a Linker)
  • Z 4 is absent.
  • Z 4 is C(O).
  • q' is 0.
  • q' is 1.
  • q' is 2.
  • q' is 3.
  • each R 17 is independently C 1 -C 3 alkyl selected from methyl, ethyl, and propyl.
  • R 18 is methyl, ethyl, or propyl. In one embodiment, R 18 is methyl.
  • the Degron is of Formula D2a:
  • each R 17 is independently C 1 -C 3 alkyl
  • q' is 0, 1, 2, 3 or 4;
  • R 18 is H or C 1 -C 3 alkyl
  • Degron is covalently bonded to another moiety (e.g., a compound, or a Linker)
  • another moiety e.g., a compound, or a Linker
  • q' is 0.
  • q' is 1.
  • q' is 2.
  • q' is 3.
  • each R 17 is independently C 1 -C 3 alkyl selected from methyl, ethyl, and propyl.
  • R 18 is methyl, ethyl, or propyl. In one embodiment, R 18 is methyl. In one embodiment, the Degron is of Formula D2b:
  • each R17 is independently C1-C3 alkyl
  • q' is 0, 1, 2, 3 or 4;
  • R18 is H or C1-C3 alkyl
  • Degron is covalently bonded to another moiety (e.g., a compound, or a Linker)
  • another moiety e.g., a compound, or a Linker
  • q' is 0.
  • q' is 1.
  • q' is 2.
  • q' is 3.
  • each R17 is independently C1-C3 alkyl selected from methyl, ethyl, and propyl.
  • R18 is methyl, ethyl, or propyl. In one embodiment, R18 is methyl.
  • Linker is a bond, a carbon chain, carbocyclic ring, or heterocyclic ring that serves to link a Targeting Ligand with a Degron.
  • the carbon chain optionally comprises one, two, three, or more heteroatoms selected from N, O, and S.
  • the carbon chain comprises only saturated chain carbon atoms.
  • the carbon chain optionally comprises two or more unsaturated chain carbon atoms (e.g., C C or C C ).
  • one or more chain carbon atoms in the carbon chain are optionally substituted with one or more substituents (e.g., oxo, C1-C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 3 alkoxy, OH, halogen, NH 2 , NH(C 1 -C 3 alkyl), N(C 1 -C 3 alkyl) 2 , CN, C 3 -C 8 cycloalkyl, heterocyclyl, phenyl, and heteroaryl).
  • substituents e.g., oxo, C1-C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 3 alkoxy, OH, halogen, NH 2 , NH(C 1 -C 3 alkyl), N(C 1 -C 3 alkyl) 2 , CN, C 3 -C
  • the Linker comprises at least 5 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises less than 25 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises less than 20 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 chain atoms (e.g., C, O, N, and S).
  • the Linker comprises 5, 7, 9, 11, 13, 15, 17, or 19 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 5, 7, 9, or 11 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 11, 13, 15, 17, or 19 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 11, 13, 15, 17, 19, 21, or 23 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 chain atoms (e.g., C, O, N, and S).
  • the Linker comprises 6, 8, 10, 12, 14, 16, 18, or 20 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 6, 8, 10, or 12 chain atoms (e.g., C, O, N, and S). In one embodiment, the Linker comprises 12, 14, 16, 18, or 20 chain atoms (e.g., C, O, N, and S).
  • the Linker comprises from 11 to 19 chain atoms (e.g., C, O, N, and S).
  • the Linker is a carbon chain optionally substituted with non- bulky substituents (e.g., oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 3 alkoxy, OH, halogen, NH 2 , NH(C 1 -C 3 alkyl), N(C 1 -C 3 alkyl) 2 , and CN).
  • the non- bulky substitution is located on the chain carbon atom proximal to the Degron (i.e., the carbon atom is separated from the carbon atom to which the Degron is bonded by at least 3, 4, or 5 chain atoms in the Linker).
  • the non-bulky substitution is located on the chain carbon atom proximal to the Ta ng Ligand (i.e., the carbon atom is separated from the carbon atom to which the Degron is bonded by at least 3, 4, or 5 chain atoms in the Linker).
  • p1 is an integer selected from 0 to 12;
  • p2 is an integer selected from 0 to 12;
  • p3 is an integer selected from 1 to 6;
  • each W is independently absent, CH 2 , O, S, or NR 19 ;
  • Z 1 is absent, C(O), CH 2 , O, (CH 2 ) j NR 19 , O(CH 2 ) j C(O)NR 19 , C(O)NR 19 ,
  • each R 19 is independently H or C 1 -C 3 alkyl
  • s1 and s2 are each independently 1, 2, or 3;
  • j is 1, 2, or 3;
  • k is 1, 2, or 3;
  • Q is absent, NHC(O)CH 2 , or O(CH 2 ) 1-2 ; wherein the Linker is covalently bonded to a Degron via the next to Q, and covalently bonded to a Targeting Ligand via the next to Z 1 .
  • the total number of chain atoms in the Linker is less than 30. In a further embodiment, the total number of chain atoms in the Linker is less than 20.
  • p1 is an integer selected from 0 to 10.
  • p1 is an integer selected from 1 to 10.
  • p1 is selected from 1, 2, 3, 4, 5, and 6.
  • p1 is 0, 1, 3, or 5.
  • p1 is 0, 1, 2, or 3.
  • p1 is 0.
  • p1 is 1.
  • p1 is 2.
  • p1 is 3.
  • p1 is 4.
  • p1 is 5.
  • p2 is an integer selected from 0 to 10.
  • p2 is selected from 0, 1, 2, 3, 4, 5, and 6.
  • p2 is 0, 1, 2, or 3.
  • p2 is 0.
  • p2 is 1.
  • p2 is 2.
  • p2 is 3.
  • p3 is an integer selected from 1 to 5.
  • p3 is 2, 3, 4, or 5.
  • p3 is 0, 1, 2, or 3.
  • p3 is 0.
  • p3 is 1.
  • p3 is 2.
  • p3 is 3.
  • p3 is 4.
  • At least one W is CH 2 .
  • At least one W is O.
  • At least one W is S.
  • At least one W is NH.
  • At least one W is NR 19 ; and each R 19 is independently C 1 -C 3 alkyl selected from methyl, ethyl, and propyl.
  • each W is O.
  • each W is CH2.
  • j is 1, 2, or 3.
  • j is 1.
  • j is 2.
  • j 3.
  • j is 2 or 3.
  • j is 1 or 2.
  • k is 1, 2, or 3.
  • k is 1.
  • k is 2.
  • k is 3.
  • k is 2 or 3.
  • k is 1 or 2.
  • Q is absent.
  • Q is NHC(O)CH 2 .
  • Q is O(CH 2 ) 1-2 .
  • Q is OCH 2 .
  • Q is OCH 2 CH 2 .
  • Z 1 is absent.
  • Z 1 is O(CH 2 ) j C(O)NR 19 ; and R 19 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl.
  • Z 1 is O(CH 2 ) j C(O)NR 19 ; and R 19 is H.
  • Z 1 is O(CH 2 ) j C(O)NR 19 ;
  • R 19 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j is 1.
  • Z 1 is O(CH 2 ) j C(O)NR 19 ; R 19 is H; and j is 1.
  • Z 1 is O(CH 2 ) j C(O)NR 19 ;
  • R 19 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j is 2.
  • Z 1 is O(CH 2 ) j C(O)NR 19 ; R 19 is H; and j is 2.
  • Z 1 is O(CH 2 ) j C(O)NR 19 ;
  • R 19 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j is 3.
  • Z1 is O(CH2)jC(O)NR19; and R19 is H; and j is 3.
  • Z 1 is C(O)NR 19 ; and R 19 is H.
  • Z1 is C(O)NR19; and R19 is C1-C3 alkyl selected from methyl, ethyl, and propyl.
  • Z1 is (CH2)jC(O)NR19; and R19 is H.
  • Z 1 is (CH 2 ) j C(O)NR 19 ; and R 19 is C 1 -C 3 alkyl selected from
  • Z 1 is (CH 2 ) j C(O)NR 19 ; R 19 is H; and j is 1.
  • Z 1 is (CH 2 ) j C(O)NR 19 ;
  • R 19 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j is 1
  • Z 1 is (CH 2 ) j C(O 9 ; R 19 is H; and j is 2.
  • Z 1 is (CH 2 ) j C(O)NR 19 ; R 19 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j is 2.
  • Z 1 is (CH 2 ) j C(O)NR 19 ; R 19 is H; and j is 3.
  • Z 1 is (CH 2 ) j C(O)NR 19 ;
  • R 19 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j is 3.
  • Z 1 is NR 19 C(O); and R 19 is H.
  • Z1 is NR19C(O); and R19 is C1-C3 alkyl selected from methyl, ethyl, and propyl.
  • Z 1 is (CH 2 ) j NR 19 C(O); and R 19 is H.
  • Z 1 is (CH 2 ) j NR 19 C(O); and R 19 is C 1 -C 3 alkyl selected from
  • Z 1 is (CH 2 ) j NR 19 C(O); R 19 is H; and j is 1.
  • Z 1 is (CH 2 ) j NR 19 C(O); R 19 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j is 1
  • Z 1 is (CH 2 ) j NR 19 C(O); R 19 is H; and j is 2.
  • Z 1 is (CH 2 ) j NR 19 C(O); R 19 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j is 2.
  • Z 1 is (CH 2 ) j NR 19 C(O); R 19 is H; and j is 3.
  • Z 1 is (CH 2 ) j NR 19 C(O); R 19 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j is 3.
  • Z 1 is (CH 2 ) k NR 19 (CH 2 ) j C(O)NR 19 ; and each R 19 is independently H or C 1 -C 3 alkyl selected from methyl, ethyl, and propyl.
  • Z 1 is (CH 2 ) k NR 19 (CH 2 ) j C(O)NR 19 ; and one of R 19 is H and one of R19 is C1-C3 alkyl selected from methyl, ethyl, and propyl.
  • Z1 is (CH 2 ) k NR 19 (CH 2 ) j C(O)NH.
  • Z1 is (CH2)kNR19(CH2)jC(O)NR19; each R19 is independently H or C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j is 1.
  • Z1 is (CH2)kNR19(CH2)jC(O)NR19; each R19 is independently H or C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and k is 1.
  • Z 1 is (CH 2 ) k NR 19 (CH 2 ) j C(O)NR 19 ; each R 19 is independently H or C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; j is 1; and k is 1.
  • Z 1 is (CH 2 ) k NR 19 (CH 2 ) j C(O)NR 19 ; one of R 19 is H and one of R 19 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j is 1.
  • Z 1 is (CH 2 ) k NR 19 (CH 2 )C(O)NH.
  • Z 1 is (CH 2 ) k NR 19 (CH 2 ) j C(O)NR 19 ; one of R 19 is H and one of R 19 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and k is 1.
  • Z 1 is (CH 2 )NR 19 (CH 2 ) j C(O)NH.
  • Z 1 is (CH 2 ) k NR 19 (CH 2 ) j C(O)NR 19 ; one of R 19 is H and one of R 19 is C1-C3 alkyl selected from methyl, ethyl, and propyl; j is 1; and k is 1.
  • Z 1 is (CH 2 )NR 19 (CH 2 )C(O)NH.
  • Z 1 is
  • Z 1 is (CH 2 ) k NR 19 (CH 2 ) j C(O)NR 19 ; each R 19 is independently H or C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j is 2.
  • Z 1 is (CH 2 ) k NR 19 (CH 2 ) j C(O)NR 19 ; each R 19 is independently H or C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and k is 2.
  • Z 1 is (CH 2 ) k NR 19 (CH 2 ) j C(O)NR 19 ; one of R 19 is H and one of R 19 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j is 2. In one embodiment, Z 1 is (CH 2 ) k NR 19 (CH 2 ) 2 C(O)NH.
  • Z 1 is (CH 2 ) k NR 19 (CH 2 ) j C(O)NR 19 ; one of R 19 is H and one of R 19 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and k is 2. In one embodiment, Z 1 is (CH 2 ) 2 NR 19 (CH 2 ) j C(O)NH.
  • Z 1 is (CH 2 ) k NR 19 (CH 2 ) j C(O)NR 19 ; each R 19 is independently H or C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j is 3.
  • Z 1 is (CH 2 ) k NR 19 (CH 2 ) j C(O)NR 19 ; each R 19 is independently H or C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and k is 3.
  • Z 1 is (CH 2 ) k NR 19 (CH 2 ) j C(O)NR 19 ; one of R 19 is H and one of R 19 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j is 3. In one embodiment, Z 1 is (CH2)kNR19(CH2)3C(O)NH.
  • Z 1 is (CH 2 ) k NR 19 (CH 2 ) j C(O)NR 19 ; one of R 19 is H and one of R 19 is C1-C3 alkyl selected from methyl, ethyl, and propyl; and k is 3.
  • Z1 is (CH 2 ) 3 NR 19 (CH 2 ) j C(O)NH.
  • Z1 is NR19(CH2)jC(O)NR19; and each R19 is independently H or C 1 -C 3 alkyl selected from methyl, ethyl, and propyl.
  • Z 1 is NR 19 (CH 2 ) j C(O)NR 19 ; and each R 19 is H.
  • Z 1 is NR 19 (CH 2 ) j C(O)NR 19 ; one of R 19 is H and one of R 19 is C 1 - C 3 alkyl selected from methyl, ethyl, and propyl; and j is 1.
  • Z 1 is NR 19 (CH 2 ) j C(O)NR 19 ; R 19 is H; and j is 1. (100) In one embodiment, Z 1 is NR 19 (CH 2 ) j C(O)NR 19 ; one of R 19 is H and one of R 19 is C 1 - C 3 alkyl selected from methyl, ethyl, and propyl; and j is 2.
  • (101) in one embodiment, is NR 19 (CH 2 ) j C(O)NR 19 ; R 19 is H; and j is 2.
  • Z 1 is NR 19 (CH 2 ) j C(O)NR 19 ; one of R 19 is H and one of R 19 is C 1 - C3 alkyl selected from methyl, ethyl, and propyl; and j is 3.
  • Z 1 is NR 19 (CH 2 ) j C(O)NR 19 ; and R 19 is H; and j is 3.
  • Z 1 and R 19 are as defined in (104), and s1 is 1.
  • Z1 and R19 are defined in (104), s1 is 1; and s2 is 1.
  • Z 1 is as defined in (104), s1 is 1; and s2 is 2.
  • Z1 and R19 are as defined in (104), s1 is 1; and s2 is 3.
  • Z 1 and R 19 are as defined in (104), and s1 is 2.
  • Z 1 and R 19 are as defined in (104), s1 is 2; and s2 is 1.
  • Z 1 and R 19 are as defined in (104), s1 is 2; and s2 is 2.
  • Z 1 and R 19 are as defined in (104), s1 is 2; and s2 is 3.
  • Z 1 and R 19 are as defined in (104), and s1 is 3.
  • Z 1 and R 19 are as defined in (104), s1 is 3; and s2 is 1.
  • Z 1 and R 19 are as defined in (104), s1 is 3; and s2 is 2.
  • Z 1 and R 19 are as defined in (104), s1 is 3; and s2 is 3.
  • Z 1 and R 19 are as defined in (104), s1 is 1; s2 is 1; and j is 1.
  • Z 1 and R 19 are as defined in (104), s1 is 1; s2 is 1; and j is 2.
  • Z 1 and R 19 are as defined in (104), s1 is 1; s2 is 1; and j is 3.
  • R 19 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl.
  • Z 1 and R 19 are as defined in (120), and s1 is 1.
  • Z 1 and R 19 are as defined in (120), s1 is 1; and s2 is 1.
  • Z 1 and R 19 are as defined in (120), s1 is 1; and s2 is 2.
  • Z 1 and R 19 are as defined in (120), s1 is 1; and s2 is 3.
  • Z 1 and R 19 are as defined in (120), and s1 is 2. (126) In one embodiment, Z 1 and R 19 are as defined in (120), s1 is 2; and s2 is 1.
  • Z 1 and R 19 are as defined in (120), s1 is 2; and s2 is 2.
  • Z 1 and R 19 are as defined in (120), s1 is 2; and s2 is 3.
  • Z 1 and R 19 are as defined in (120), and s1 is 3.
  • Z1 and R19 are as defined in (120), s1 is 3; and s2 is 1.
  • Z 1 and R 19 are as defined in (120), s1 is 3; and s2 is 2.
  • Z1 and R19 are as defined in (120), s1 is 3; and s2 is 3.
  • Z 1 and R 19 are as defined in (120), s1 is 1; s2 is 1; and j is 1.
  • Z 1 and R 19 are as defined in (120), s1 is 1; s2 is 1; and j is 2.
  • Z 1 is part of the Targeting Ligand that is bonded to the Linker, namely, Z 1 is formed from reacting a functional group of the Targeting Ligand with the Linker.
  • p1 is 1 and Z 1 is (CH 2 ) j C(O)NH.
  • p1 is 1 and Z 1 is (CH 2 )C(O)NH.
  • p1 is 1 and Z 1 is (CH 2 ) 2 C(O)NH.
  • p1 is 1 and Z 1 is (CH 2 ) 3 C(O)NH.
  • p1 is 1
  • Z 1 is (CH 2 ) j C(O)NH
  • p3 is 1.
  • p1 is 1
  • Z 1 is (CH 2 )C(O)NH
  • p3 is 1.
  • p1 is 1
  • Z 1 is (CH 2 ) 2 C(O)NH
  • p3 is 1.
  • p1 is 1
  • Z 1 is (CH 2 ) j C(O)NH
  • p3 is 1
  • p2 is 0.
  • p1 is 1
  • Z 1 is (CH 2 )C(O)NH
  • p3 is 1
  • p2 is 0.
  • p1 is 1
  • Z 1 is (CH 2 ) 2 C(O)NH
  • p3 is 1
  • p2 is 0.
  • p1 is 1, Z1 is (CH2)jC(O)NH, p3 is 1, p2 is 0, and each W is O.
  • p1 is 1, Z 1 is (CH 2 )C(O)NH, p3 is 1, p2 is 0, and each W is O.
  • p1 is 1, Z1 is (CH2)2C(O)NH, p3 is 1, p2 is 0, and each W is O.
  • p1 is 1, Z 1 is (CH2)2C(O)NH, p3 is 1, p2 is 0, and each W is O.
  • p1 is 1, Z 1 is (CH 2 ) j C(O)NH, p3 is 1, p2 is 0, and each W is CH 2 .
  • p1 is 1, Z1 is (CH2)C(O)NH, p3 is 1, p2 is 0, and each W is CH2.
  • p1 is 1, Z 1 is (CH 2 ) 2 C(O)NH, p3 is 1, p2 is 0, and each W is CH 2 .
  • p1 is 2 and Z 1 is (CH 2 )C(O)NH.
  • p1 is 2 and Z 1 is (CH 2 ) 2 C(O)NH.
  • p1 is 2 and Z 1 is (CH 2 ) 3 C(O)NH.
  • p1 is 2
  • Z 1 is (CH 2 ) j C(O)NH
  • p3 is 2.
  • p1 is 2, Z 1 is (C (O)NH, and p3 is 2.
  • p1 is 2, Z 1 is (CH 2 ) 2 C(O)NH, and p3 is 2.
  • p1 is 2
  • Z 1 is (CH 2 ) j C(O)NH
  • p3 is 2
  • p2 is 0.
  • p1 is 2
  • Z 1 is (CH 2 )C(O)NH
  • p3 is 2
  • p2 is 0.
  • p1 is 2
  • Z 1 is (CH 2 ) 2 C(O)NH
  • p3 is 2
  • p2 is 0.
  • p1 is 2, Z1 is (CH2)jC(O)NH, p3 is 2, p2 is 0, and each W is O. (163) In one embodiment, p1 is 2, Z 1 is (CH 2 )C(O)NH, p3 is 2, p2 is 0, and each W is O. (164) In one embodiment, p1 is 2, Z1 is (CH2)2C(O)NH, p3 is 2, p2 is 0, and each W is O. (165) In one embodiment, p1 is 2, Z 1 is (CH 2 ) j C(O)NH, p3 is 2, p2 is 0, and each W is CH 2 .
  • p1 is 2, Z 1 is (CH 2 )C(O)NH, p3 is 2, p2 is 0, and each W is CH 2 .
  • p1 is 2, Z 1 is (CH 2 ) 2 C(O)NH, p3 is 2, p2 is 0, and each W is CH 2 .
  • p1 is 3 and Z 1 is (CH 2 )C(O)NH.
  • p1 is 3 and Z 1 is (CH 2 ) 2 C(O)NH.
  • p1 is 3 and Z 1 is (CH 2 ) 3 C(O)NH.
  • p1 is 3
  • Z 1 is (CH 2 ) j C(O)NH
  • p3 is 3.
  • p1 is 3
  • Z 1 is (CH 2 )C(O)NH
  • p3 is 3.
  • p1 is 3
  • Z 1 is (CH 2 ) 2 C(O)NH
  • p3 is 3.
  • p1 is 3
  • Z 1 is (CH 2 ) j C(O)NH
  • p3 is 3
  • p2 is 1.
  • p1 is 3
  • Z 1 is (CH 2 )C(O)NH
  • p3 is 3
  • p2 is 1.
  • p1 is 3
  • Z 1 is (CH 2 ) 2 C(O)NH
  • p3 is 3
  • p2 is 1.
  • p1 is 3, Z 1 is (CH 2 ) j C(O)NH, p3 is 3, p2 is 1, and each W is O.
  • p1 is 3, Z 1 is (CH 2 )C(O)NH, p3 is 3, p2 is 1, and each W is O.
  • p1 is 3, Z 1 is (CH 2 ) 2 C(O)NH, p3 is 3, p2 is 1, and each W is O.
  • p1 is 3, Z 1 is (CH 2 ) j C(O)NH, p3 is 3, p2 is 1, and each W is CH 2 .
  • p1 is 3, Z1 is (CH2)C(O)NH, p3 is 3, p2 is 1, and each W is CH2.
  • p1 is 3, Z 1 is (CH 2 ) 2 C(O)NH, p3 is 3, p2 is 1, and each W is CH 2 .
  • p1 is 2, Z1 is (CH2)jC(O)NH, and p3 is 1.
  • p1 is 2
  • Z 1 is (CH 2 )C(O)NH
  • p3 is 1.
  • p1 is 2
  • Z1 is (CH2)2C(O)NH
  • p3 is 1.
  • p1 is 2
  • Z 1 is (CH 2 ) j C(O)NH
  • p3 is 1
  • p2 is 1.
  • p1 is 2
  • Z 1 is (CH 2 )C(O)NH
  • p3 is 1
  • p2 is 1.
  • p1 is 2
  • Z 1 is (CH 2 ) 2 C(O)NH
  • p3 is 1
  • p2 is 1.
  • p1 is 2, Z 1 is (CH 2 ) j C(O)NH, p3 is 1, p2 is 1, and each W is O.
  • p1 is 2, Z 1 is (CH 2 )C(O)NH, p3 is 1, p2 is 1, and each W is O. (191)
  • p1 is 2, Z 1 is (C C(O)NH, p3 is 1, p2 is 1, and each W is O. (192)
  • p1 is 2, Z 1 is (CH 2 ) j C(O)NH, p3 is 1, p2 is 1, and each W is CH 2 .
  • p1 is 2, Z 1 is (CH 2 )C(O)NH, p3 is 1, p2 is 1, and each W is CH 2 . (194) In one embodiment, p1 is 2, Z 1 is (CH 2 ) 2 C(O)NH, p3 is 1, p2 is 1, and each W is CH 2 . (195) In one embodiment, p1 is 1, Z 1 is (CH 2 ) j C(O)NH, and p3 is 2.
  • p1 is 1, Z1 is (CH2)C(O)NH, and p3 is 2.
  • p1 is 1, Z 1 is (CH 2 ) 2 C(O)NH, and p3 is 2.
  • p1 is 1, Z1 is (CH2)jC(O)NH, p3 is 2, and p2 is 0.
  • p1 is 1, Z 1 is (CH 2 )C(O)NH, p3 is 2, and p2 is 0.
  • p1 is 1
  • Z 1 is (CH 2 ) 2 C(O)NH
  • p3 is 2
  • p2 is 0.
  • p1 is 1, Z 1 is (CH 2 ) j C(O)NH, p3 is 2, p2 is 0, and each W is O.
  • p1 is 1, Z 1 is (CH 2 )C(O)NH, p3 is 2, p2 is 0, and each W is O.
  • p1 is 1, Z 1 is (CH 2 ) 2 C(O)NH, p3 is 2, p2 is 0, and each W is O.
  • p1 is 1, Z 1 is (CH 2 ) j C(O)NH, p3 is 2, p2 is 0, and each W is CH 2 .
  • p1 is 1, Z 1 is (CH 2 )C(O)NH, p3 is 2, p2 is 0, and each W is CH 2 .
  • p1 is 1, Z 1 is (CH 2 ) 2 C(O)NH, p3 is 2, p2 is 0, and each W is CH 2 .
  • p1 is 1, Z 1 is (CH 2 ) j C(O)NH, and p3 is 3.
  • p1 is 1, Z 1 is (CH 2 )C(O)NH, and p3 is 3.
  • p1 is 1
  • Z 1 is (CH 2 ) 2 C(O)NH
  • p3 is 3.
  • p1 is 1
  • Z 1 is (CH 2 ) j C(O)NH
  • p3 is 3
  • p2 is 0.
  • p1 is 1
  • Z 1 is (CH 2 )C(O)NH
  • p3 is 3
  • p2 is 0.
  • p1 is 1
  • Z 1 is (CH 2 ) 2 C(O)NH
  • p3 is 3
  • p2 is 0.
  • p1 is 1, Z 1 is (CH 2 ) j C(O)NH, p3 is 3, p2 is 0, and each W is O.
  • p1 is 1, Z 1 is (CH 2 )C(O)NH, p3 is 3, p2 is 0, and each W is O.
  • p1 is 1, Z1 is (CH2)2C(O)NH, p3 is 3, p2 is 0, and each W is O.
  • p1 is 1, Z 1 is (CH 2 ) j C(O)NH, p3 is 3, p2 is 0, and each W is CH 2 .
  • p1 is 1, Z1 is (CH2)C(O)NH, p3 is 3, p2 is 0, and each W is CH2.
  • p1 is 1, Z 1 is (CH 2 ) 2 C(O)NH, p3 is 3, p2 is 0, and each W is CH 2 .
  • p1 is 4 and Z1 is (CH2)C(O)NH.
  • p1 is 4 and Z 1 is (CH 2 ) 2 C(O)NH.
  • p1 is 4 and Z 1 is (CH 2 ) 3 C(O)NH.
  • p1 is 4
  • Z 1 is (CH 2 ) j C(O)NH
  • p3 is 2.
  • p1 is 4
  • Z 1 is (CH 2 )C(O)NH
  • p3 is 2.
  • p1 is 4
  • Z 1 is (CH 2 ) 2 C(O)NH
  • p3 is 2.
  • p1 is 4, Z 1 is (C (O)NH, p3 is 2, and p2 is 0.
  • p1 is 4, Z 1 is (CH 2 )C(O)NH, p3 is 2, and p2 is 0.
  • p1 is 4
  • Z 1 is (CH 2 ) 2 C(O)NH
  • p3 is 2
  • p2 is 0.
  • p1 is 4, Z 1 is (CH 2 ) j C(O)NH, p3 is 2, p2 is 0, and each W is O.
  • p1 is 4, Z 1 is (CH 2 )C(O)NH, p3 is 2, p2 is 0, and each W is O.
  • p1 is 4, Z1 is (CH2)2C(O)NH, p3 is 2, p2 is 0, and each W is O.
  • p1 is 4, Z 1 is (CH 2 ) j C(O)NH, p3 is 2, p2 is 0, and each W is CH 2 .
  • p1 is 4, Z1 is (CH2)C(O)NH, p3 is 2, p2 is 0, and each W is CH2.
  • p1 is 4, Z 1 is (CH 2 ) 2 C(O)NH, p3 is 2, p2 is 0, and each W is CH 2 .
  • p1 is 3, Z 1 is (CH 2 ) j C(O)NH, and p3 is 2.
  • p1 is 3
  • Z 1 is (CH 2 )C(O)NH
  • p3 is 2.
  • p1 is 3
  • Z 1 is (CH 2 ) 2 C(O)NH
  • p3 is 2.
  • p1 is 3
  • Z 1 is (CH 2 ) j C(O)NH
  • p3 is 2
  • p2 is 0.
  • p1 is 3
  • Z 1 is (CH 2 )C(O)NH
  • p3 is 2
  • p2 is 0.
  • p1 is 3
  • Z 1 is (CH 2 ) 2 C(O)NH
  • p3 is 2
  • p2 is 0.
  • p1 is 3, Z 1 is (CH 2 ) j C(O)NH, p3 is 2, p2 is 0, and each W is O.
  • p1 is 3, Z 1 is (CH 2 )C(O)NH, p3 is 2, p2 is 0, and each W is O.
  • p1 is 3, Z 1 is (CH 2 ) 2 C(O)NH, p3 is 2, p2 is 0, and each W is O.
  • p1 is 3, Z 1 is (CH 2 ) j C(O)NH, p3 is 2, p2 is 0, and each W is CH 2 .
  • p1 is 3, Z 1 is (CH 2 )C(O)NH, p3 is 2, p2 is 0, and each W is CH 2 .
  • p1 is 3, Z 1 is (CH 2 ) 2 C(O)NH, p3 is 2, p2 is 0, and each W is CH 2 .
  • p1 is 1, Z 1 is (CH 2 ) j C(O)NH, and p3 is 2.
  • p1 is 1, Z 1 is (CH 2 )C(O)NH, and p3 is 2.
  • p1 is 1, Z 1 is (CH 2 ) 2 C(O)NH, and p3 is 2.
  • p1 is 1
  • Z1 is (CH2)jC(O)NH
  • p3 is 2
  • p2 is 1.
  • p1 is 1
  • Z 1 is (CH 2 )C(O)NH
  • p3 is 2
  • p2 is 1.
  • p1 is 1
  • Z1 is (CH2)2C(O)NH
  • p3 is 2
  • p2 is 1.
  • p1 is 1, Z 1 is (CH 2 ) j C(O)NH, p3 is 2, p2 is 1, and each W is O.
  • p1 is 1, Z1 is (CH2)C(O)NH, p3 is 2, p2 is 1, and each W is O.
  • p1 is 1, Z 1 is (CH 2 ) 2 C(O)NH, p3 is 2, p2 is 1, and each W is O.
  • p1 is 1, Z 1 is (CH 2 ) j C(O)NH, p3 is 2, p2 is 1, and each W is CH 2 .
  • p1 is 1, Z 1 is (CH 2 )C(O)NH, p3 is 2, p2 is 1, and each W is CH 2 .
  • p1 is 1, Z 1 is (CH 2 ) 2 C(O)NH, p3 is 2, p2 is 1, and each W is CH 2 .
  • p1 is 3, Z 1 is O(CH 2 )C(O)NH, p3 is 2, p2 is 0, and each W is O.
  • p1 is 3, Z 1 is O(CH 2 )C(O)NH, p3 is 2, p2 is 0, and each W is CH 2 .
  • p1 is 2, Z 1 is O(CH 2 )C(O)NH, p3 is 2, p2 is 0, and each W is O.
  • p1 is 2, Z 1 is O(CH 2 )C(O)NH, p3 is 2, p2 is 0, and each W is CH2.
  • p1 is 1, Z 1 is O(CH 2 )C(O)NH, p3 is 3, p2 is 0, and each W is O.
  • p1 is 1, Z1 is O(CH2)C(O)NH, p3 is 3, p2 is 0, and each W is CH 2 .
  • p1 is 2
  • Z 1 is (CH 2 )N(CH 3 )CH 2 C(O)NH
  • p3 is 2
  • p2 is 0, and each W is CH 2 .
  • p1 is 2
  • Z 1 is (CH 2 )N(CH 3 )CH 2 C(O)NH
  • p3 is 2
  • p2 is 0, and each W is O.
  • p1 is 2, Z 1 is C(O)NH, p3 is 2, p2 is 0, and each W is CH 2 .
  • p1 is 2, Z 1 is C(O)NH, p3 is 2, p2 is 0, and each W is O.
  • p1, Z 1 , p3, p2, and W are each as defined, where applicable, in any one of (1)-(267), and Q is absent.
  • p1, Z 1 , p3, p2, and W are each as defined, where applicable, in any one of (1)-(267), and Q is NHC(O)CH 2 .
  • p1, Z 1 , p3, p2, and W are each as defined, where applicable, in any one of (1)-(267), and Q is O(CH 2 ) 1-2 .
  • p1, Z 1 , p3, p2, and W are each as defined, where applicable, in any one of (1)-(267), and Q is O(CH 2 ).
  • p1, Z 1 , p3, p2, and W are each as defined, where applicable, in any one of (1)-(267), and Q is O(CH2CH2).
  • the Linker–Targeting Ligand has the structure selected from Table L:
  • Z 1 , W, Q, TL, p1, p3, and j are each as described above.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1, and the Linker is selected from L1a– L1k and L1m– L1y. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1, and the Linker is selected from L1a– L1k and L1m– L1u. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1, and the Linker is selected from L1a– L1k, L1m, and L1n.
  • the Degron is of Formula D1, and the Linker is selected from L1a– L1k and L1m– L1u. In one embodiment, the Degron is of Formula D1, and the Linker is selected from L1a– L1k, L1m, and L1n. In one embodiment, the Degron is of Formula D1, and the Linker is L1a, L1b, or L1c. In one embodiment, the Degron is of Formula D1, and the Linker is L1d, L1e, or L1f. In one embodiment, the Degron is of Formula D1, and the Linker is L1g or L1h. In one embodiment, the Degron is of Formula D1, and the Linker is L1i, L1j, or L1k.
  • the Degron is of Formula D1, and the Linker is L1m or L1n. In one embodiment, the Degron is of Formula D1, and the Linker is L1o-L1u. In one embodiment, the Degron is of Formula D1, and the Linker is L1o or L1p. In one embodiment, the Degron is of Formula D1, and the Linker is L1p or L1q. In one embodiment, the Degron is of Formula D1, and the Linker is L1r or L1s. In one embodiment, the Degron is of Formula D1, and the Linker is L1t or L1u. In one embodiment, the Degron is of Formula D1, and the Linker is L1v-L1y.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L1a– L1k and L1m– L1y.
  • DL Degron-Linker
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L1a– L1k and L1m– L1u.
  • DL Degron-Linker
  • the present application provides the Degron- Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L1a– L1k, L1m, and L1n.
  • the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L1a– L1k and L1m– L1u.
  • the Degron is of Formula D1a, D1b, D1c, D 1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L1a– L1k, L1m, and L1n.
  • the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1a, L1b, or L1c.
  • the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1d, L1e, or L1f.
  • the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1g or L1h.
  • the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1i, L1j, or L1k.
  • the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1m or L1n.
  • the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1o-L1u.
  • the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1o or L1p.
  • the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1p or L1q.
  • the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1r or L1s.
  • the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1t or L1u.
  • the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is L1v-L1y.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2, and the Linker is selected from L1a– L1k and L1m– L1y. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2, and the Linker is selected from L1a– L1k and L1m– L1u. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2, and the Linker is selected from L1a– L1k, L1m, and L1n.
  • the Degron is of Formula D2, and the Linker is selected from L1a– L1k and L1m– L1u. In one embodiment, the Degron is of Formula D2, and the Linker is selected from L1a– L1k, L1m, and L1n. In one embodiment, the Degron is of Formula D2, and the Linker is L1a, L1b, or L1c. In one embodiment, the Degron is of Formula D2, and the Linker is L1d, L1e, or L1f. In one embodiment, the Degron is of Formula D2, and the Linker is L1g or L1h. In one embodiment, the Degron is of Formula D2, and the Linker is L1i, L1j, or L1k.
  • the Degron is of Formula D2, and the Linker is L1m or L1n. In one embodiment, the Degron is of Formula D2, and the Linker is L1o-L1u. In one embodiment, the Degron is of Formula D2, and the Linker is L1o or L1p. In one embodiment, the Degron is of Formula D2, and the Linker is L1p or L In one embodiment, the Degron is of Formula D2, and the Linker is L1r or L1s. In one embodiment, the Degron is of Formula D2, and the Linker is L1t or L1u. In one embodiment, the Degron is of Formula D2, and the Linker is L1v-L1y.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2a or D2b, and the Linker is selected from L1a– L1k and L1m– L1y.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2a or D2b, and the Linker is selected from L1a– L1k and L1m– L1u.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2a or D2b, and the Linker is selected from L1a– L1k, L1m, and L1n.
  • the Degron is of Formula D2a or D2b, and the Linker is selected from L1a– L1k and L1m– L1u. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is selected from L1a– L1k, L1m, and L1n. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L1a, L1b, or L1c. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L1d, L1e, or L1f. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is selected from L1a– L1k and L1m– L1u. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is selected from L1a– L1k, L1m, and L1n. In one embodiment, the Degron is of Formula D2a
  • the Degron is of Formula D2a or D2b, and the Linker is L1g or L1h. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L1i, L1j, or L1k. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L1m or L1n. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L1o-L1u. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L1o or L1p.
  • the Degron is of Formula D2a or D2b, and the Linker is L1p or L1q. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L1r or L1s. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L1t or L1u. In one embodiment, the Degron is of Formula D2a or D2b, and the Linker is L1v-L1y.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2c or D2d, and the Linker is selected from L1a– L1k and L1m– L1y.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2c or D2d, and the Linker is selected from L1a– L1k and L1m– L1u.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2c or D2d, and the Linker is selected from L1a– L1k, L1m, and L1n.
  • the Degron is of Formula D2c or D2d, and the Linker is selected from L1a– L1k and L1m– L1u. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is selected from L1a– L1k, L1m, and L1n. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L1a, L1b, or L1c. In one embodiment, the Degron is of Formula D2c or D2d, and t nker is L1d, L1e, or L1f.
  • the Degron is of Formula D2c or D2d, and the Linker is L1g or L1h. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L1i, L1j, or L1k. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L1m or L1n. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L1o-L1u. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L1o or L1p.
  • the Degron is of Formula D2c or D2d, and the Linker is L1p or L1q. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L1r or L1s. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L1t or L1u. In one embodiment, the Degron is of Formula D2c or D2d, and the Linker is L1v-L1y.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2e or D2f, and the Linker is selected from L1a– L1k and L1m– L1y.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2e or D2f, and the Linker is selected from L1a– L1k and L1m– L1u.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2e or D2f, and the Linker is selected from L1a– L1k, L1m, and L1n.
  • the Degron is of Formula D2e or D2f, and the Linker is selected from L1a– L1k and L1m– L1u. In one embodiment, the Degron is of Formula D2e or D2f, and the Linker is selected from L1a– L1k, L1m, and L1n. In one embodiment, the Degron is of Formula D2e or D2f, and the Linker is L1a, L1b, or L1c. In one embodiment, the Degron is of Formula D2e or D2f, and the Linker is L1d, L1e, or L1f. In one embodiment, the Degron is of Formula D2e or D2f, and the Linker is L1g or L1h.
  • the Degron is of Formula D2e or D2f, and the Linker is L1i, L1j, or L1k. In one embodiment, the Degron is of Formula D2e or D2f, and the Linker is L1m or L1n. In one embodiment, the Degron is of Formula D2e or D2f, and the Linker is L1o-L1u. In one embodiment, the Degron is of Formula D2e or D2f, and the Linker is L1o or L1p. In one embodiment, the Degron is of Formula D2e or D2f, and the Linker is L1p or L1q.
  • the Degron is of Formula D2e or D2f, and the Linker is L1r or L1s. In one embodiment, the Degron is of Formula D2e or D2f, and the Linker is L1t or L1u. In one embodiment, the Degron is of Formula D2e or D2f, and the Linker is L1v-L1y.
  • the Linker is of Formula L2:
  • Z 2 is absent, C(O), CH 2 , O(CH 2 ) j1 C(O), or NR 20 (CH 2 ) j1 C(O);
  • R 20 is H or C 1 -C 3 alkyl
  • j 1 is 1, 2, or 3;
  • Q2 is absent, NHC(O)CH2, or C(O)(CH2)1-4; wherein the Linker is covalently bonded to a Degron via the next to Q 2 , and covalently bonded to a Targeting Ligand via the next to Z 2 .
  • s3 is 0.
  • s3 is 1.
  • Z 2 is absent.
  • Z 2 is CH 2 .
  • Z 2 is C(O).
  • Z 2 is O(CH 2 ) j1 C(O). In one embodiment, Z 2 is O(CH 2 )C(O). In one embodiment, Z is NR 20 (CH 2 ) j1 C(O).
  • Z 2 is NR 20 (CH 2 ) j1 C(O); and R 20 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl.
  • Z 2 is NR 20 (CH 2 ) j1 C(O); and R 20 is H.
  • Z 2 is NR 20 (CH 2 ) j1 C(O); R 20 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j 1 is 1.
  • Z 2 is NR 20 (CH 2 ) j1 C(O); R 20 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j 1 is 2.
  • Z2 is NR20(CH2)j1C(O); R20 is C1-C3 alkyl selected from methyl, ethyl, and propyl; and j 1 is 3.
  • Z2 is NR20(CH2)j1C(O); R20 is H; and j1 is 1.
  • Z 2 is NR 20 (CH 2 ) j1 C(O); R 20 is H; and j 1 is 2.
  • Z 2 is NR 20 (CH 2 ) j1 C(O); R 20 is H; and j 1 is 3.
  • Q 2 is absent.
  • Q 2 is C(O)(CH 2 ) 1-4 .
  • Q 2 is NHC(O)CH 2 .
  • s3 is 0 and Q 2 is absent.
  • s3 is 0 and Q 2 is C(O)(CH 2 ) 1-4 . In one embodiment, s3 is 0 and Q 2 is NHC(O)CH 2 .
  • s3 is 1 and Q 2 is absent.
  • s3 is 1 and Q 2 is C(O)(CH 2 ) 1-4 .
  • s3 is 1 and Q 2 is NHC(O)CH 2 .
  • Q2 is absent and Z is absent.
  • Q 2 is absent and Z is CH 2 .
  • Q2 is absent and Z is C(O).
  • Q 2 is absent and Z is O(CH 2 ) j1 C(O).
  • Q 2 is absent and Z is NR 20 (CH 2 ) j1 C(O).
  • Q 2 is C(O)(CH 2 ) 1-4 and Z is absent.
  • Q 2 is C(O)(CH 2 ) 1-4 and Z is CH 2 .
  • Q 2 is C(O)(CH 2 ) 1-4 and Z is C(O).
  • Q 2 is C(O)(CH 2 ) 1-4 and Z is O(CH 2 ) j1 C(O).
  • Q 2 is C(O)(CH 2 ) 1-4 and Z is NR 20 (CH 2 ) j1 C(O).
  • Q 2 is NHC(O)CH 2 and Z is absent.
  • Q 2 is NHC(O)CH 2 and Z is CH 2 .
  • Q 2 is NHC(O)CH 2 and Z is C(O).
  • Q 2 is NHC(O)CH 2 and Z is O(CH 2 ) j1 C(O).
  • Q 2 is NHC(O)CH 2 and Z is NR 20 (CH 2 ) j1 C(O).
  • s3 is 0 and Z 2 is absent.
  • s3 is 1 and Z 2 is absent.
  • s3 is 0 and Z 2 is CH 2 .
  • s3 is 1 and Z 2 is CH 2 .
  • s3 is 0 and Z2 is C(O).
  • s3 is 1 and Z 2 is C(O).
  • s3 is 0 and Z2 is NR20(CH2)j1C(O).
  • s3 is 1 and Z 2 is NR 20 (CH 2 ) j1 C(O).
  • the Linker–Targeting Ligand (TL) has the structure selected from Table M:
  • any one of the Degrons described herein can be covalently bound to any one of the Linkers described herein.
  • Any one of the Targeting Ligands described herein can be covalently bound to any one of the Linkers described herein.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1, and the Linker is selected from L2a– L2f. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1, and the Linker is selected from L2a. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1, and the Linker is selected from L2b or L2c. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1, and the Linker is selected from L2d or L2e.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1, and the Linker is selected from L2f. In one embodiment, the present application provide Degron-Linker (DL), wherein the Degron is of Formula D1, and the Linker is selected from L2b -L2d. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1, and the Linker is selected from L2d or L2f.
  • DL Degron-Linker
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L2a– L2f.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L2a.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L2b or L2c.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L2d or L2e.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L2f.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L2b -L2d.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L2d or L2f.
  • DL Degron-Linker
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2, and the Linker is selected from L2a– L2f. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2, and the Linker is selected from L2a. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2, and the Linker is selected from L2b or L2c. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2, and the Linker is selected from L2d or L2e.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2, and the Linker is selected from L2f. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2, and the Linker is selected from L2b -L2d. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2, and the Linker is selected from L2d or L2f. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2a or D2b, and the Linker is selected from L2a– L2f.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2a or D2b, and the Linker is selected from L2a. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2a or D2b, and the Linker is selected from L2b or L2c. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2a or D2b, and the Linker is selected from L2d or L2e. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2a or D2b, and the Linker is selected from L2f.
  • DL Degron-Linker
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2a or D2b, and the Linker is selected from L2b -L2d. In one embodiment, the present application provides the Degron- Linker (DL), wherein the Degron is of Formula D2a or D2b, and the Linker is selected from L2d or L2f.
  • DL Degron-Linker
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2c or D2d, and the Linker is selected from L2a– L2f. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2c or D2d, and the Linker is selected from L2a. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2c or D2d, and the Linker is selected from L2b or L2c.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2c or D2d, and the Linker is selected from L2d or L2e.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2c or D2d, and the Linker is selected from L2f.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2c or D2d, and the Linker is selected from L2b -L2d.
  • the present application provides the Degron- Linker (DL), wherein the Degron is of Formula D2c or D2d, and the Linker is selected from L2d or L2f.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2e or D2f, and the Linker is selected from L2a– L2f. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2e or D2f, and the Linker is selected from L2a. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2e or D2f, and the Linker is selected from or L2c.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2e or D2f, and the Linker is selected from L2d or L2e.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2e or D2f, and the Linker is selected from L2f.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2e or D2f, and the Linker is selected from L2b -L2d.
  • the present application provides the Degron- Linker (DL), wherein the Degron is of Formula D2e or D2f, and the Linker is selected from L2d or L2f.
  • the Linker is of Formula L3:
  • Z 3 is absent, C(O), CH 2 , NR 21 (CH 2 ) j2 , O(CH 2 ) j2 C(O), O(CH 2 ) j2 C(O)NR 21 , C(O)NR 21 ,
  • each R 21 is independently H or C 1 -C 3 alkyl
  • j2 is 1, 2, or 3;
  • Q 3 is absent, (CH 2 ) 1-3 , (CH 2 ) 1-3 NH, or NHC(O)CH 2 ; wherein the Linker is covalently bonded to the Degron via the next to Q 3 , and covalently bonded to the Targeting Ligand via the next to Z 3 .
  • Z 3 is absent.
  • Z 3 is C(O).
  • Z 3 is CH 2 .
  • Z 3 is NR 21 (CH 2 ) j2 .
  • Z 3 is NR 21 (CH 2 ) j21 ; and R 21 is H.
  • Z 3 is NR 21 (CH 2 ) j2 ; and R 21 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl.
  • Z 3 is NR 21 (CH 2 ) j2 ; and j2 is 1.
  • Z 3 is NR 21 (CH 2 ) j2 ; R 21 is H; and j2 is 1.
  • Z 3 is NR 21 (CH 2 ) j2 ;
  • R 21 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j2 is 1.
  • Z 3 is NR 21 (CH 2 ) j2 ; and j2 is 2.
  • Z 3 is NR 21 (CH 2 ) j2 ; R 21 is H; and j2 is 2. In one embodiment, Z 3 is NR 21 (CH 2 ) j2 ; R 21 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j2 is 2.
  • Z 3 is NR 21 (CH 2 ) j2 ; and j2 is 3.
  • Z 3 is NR 21 (CH 2 ) j2 ; R 21 is H; and j2 is 3.
  • Z3 is NR21(CH2)j2; R21 is C1-C3 alkyl selected from methyl, ethyl, and propyl; and j2 is 3.
  • Z3 is O(CH2)j2C(O).
  • Z 3 is O(CH 2 ) j2 C(O) ; and j2 is 1.
  • Z 3 is O(CH 2 ) j2 C(O) ; and j2 is 2.
  • Z 3 is O(CH 2 ) j2 C(O) ; and j2 is 3.
  • Z 3 is O(CH 2 ) j2 C(O)NR 21 .
  • Z 3 is O(CH 2 ) j2 C(O)NR 21 ; and R 21 is H.
  • Z 3 is O(CH 2 ) j2 C(O)NR 21 ; and R 21 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl.
  • Z 3 is O(CH 2 ) j2 C(O)NR 21 ; and j2 is 1.
  • Z 3 is O(CH 2 ) j2 C(O)NR 21 ; R 21 is H; and j2 is 1.
  • Z 3 is O(CH 2 ) j2 C(O)NR 21 ;
  • R 21 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j2 is 1.
  • Z 3 is O(CH 2 ) j2 C(O)NR 21 ; and j2 is 2.
  • Z 3 is O(CH 2 ) j2 C(O)NR 21 ; R 21 is H; and j2 is 2.
  • Z 3 is O(CH 2 ) j2 C(O)NR 21 ;
  • R 21 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j2 is 2.
  • Z 3 is O(CH 2 ) j2 C(O)NR 21 ; and j2 is 3.
  • Z3 is O(CH2)j2C(O)NR21; R21 is H; and j2 is 3.
  • Z 3 is O(CH 2 ) j2 C(O)NR 21 ;
  • R 21 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j2 is 3.
  • Z 3 is C(O)NR 21 .
  • Z3 is C(O)NR21; and R21 is H.
  • Z 3 is C(O)NR 21 ; and R 21 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl.
  • Z 3 is (CH 2 ) j2 C(O)NR 21 .
  • Z 3 is (CH 2 ) j2 C(O)NR 21 ; and R 21 is H.
  • Z 3 is (CH 2 ) j2 C(O)NR 21 ; and R 21 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl. In one embodiment, Z 3 is (CH 2 ) j2 C(O)NR 21 ; and j2 is 1.
  • Z 3 is (CH 2 ) j2 C(O)NR 21 ; R 21 is H; and j2 is 1.
  • Z 3 is (CH 2 ) j2 C(O)NR 21 ;
  • R 21 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j2 is 1.
  • Z3 is (CH2)j2C(O)NR21; and j2 is 2.
  • Z 3 is (CH 2 ) j2 C(O)NR 21 ; R 21 is H; and j2 is 2.
  • Z3 is (CH2)j2C(O)NR21; R21 is C1-C3 alkyl selected from methyl, ethyl, and propyl; and j2 is 2.
  • Z 3 is (CH 2 ) j2 C(O)NR 21 ; and j2 is 3.
  • Z 3 is (CH 2 ) j2 C(O)NR 21 ; R 21 is H; and j2 is 3.
  • Z 3 is (CH 2 ) j2 C(O)NR 21 ;
  • R 21 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl; and j2 is 3.
  • Z 3 is absent and Q 3 is absent.
  • Z 3 is C(O) and Q 3 is absent.
  • Z 3 is CH 2 and Q 3 is absent.
  • Z 3 is NR 21 (CH 2 ) j2 and Q 3 is absent.
  • Z 3 is O(CH 2 ) j2 C(O)NR 21 and Q 3 is absent.
  • Z 3 is O(CH 2 ) j2 C(O) and Q 3 is absent.
  • Z 3 is C(O)NR 21 and Q 3 is absent.
  • Z 3 is (CH 2 ) j2 C(O)NR 21 and Q 3 is absent.
  • Z 3 is absent and Q 3 is (CH 2 ) 1-3 .
  • Z 3 is C(O) and Q 3 is (CH 2 ) 1-3 .
  • Z 3 is CH 2 and Q 3 is (CH 2 ) 1-3 .
  • Z3 is NR21(CH2)j2 and Q3 is (CH2)1-3.
  • Z 3 is O(CH 2 ) j2 C(O)NR 21 and Q 3 is (CH 2 ) 1-3 .
  • Z3 is O(CH2)j2C(O) and Q3 is (CH2)1-3.
  • Z 3 is C(O)NR 21 and Q 3 is (CH 2 ) 1-3 .
  • Z3 is (CH2)j2C(O)NR21 and Q3 is (CH2)1-3.
  • Z 3 is absent and Q 3 is (CH 2 ) 1-3 NH.
  • Z 3 is C(O) and Q 3 is (CH 2 ) 1-3 NH.
  • Z 3 is CH 2 and Q 3 is (CH 2 ) 1-3 NH.
  • Z 3 is NR 21 (CH 2 ) j2 and Q 3 is (CH 2 ) 1-3 NH.
  • Z 3 is O(CH 2 ) j2 C(O)NR 21 and Q 3 is (CH 2 ) 1-3 NH.
  • Z 3 is O(CH 2 ) j2 C nd Q 3 is (CH 2 ) 1-3 NH. In one embodiment, Z 3 is C(O)NR 21 and Q 3 is (CH 2 ) 1-3 NH.
  • Z 3 is (CH 2 ) j2 C(O)NR 21 and Q 3 is (CH 2 ) 1-3 NH.
  • Z 3 is absent and Q 3 is NHC(O)CH 2 .
  • Z 3 is C(O) and Q 3 is NHC(O)CH 2 .
  • Z3 is CH2 and Q3 is a NHC(O)CH2.
  • Z 3 is NR 21 (CH 2 ) j2 and Q 3 is NHC(O)CH 2 .
  • Z3 is O(CH2)j2C(O)NR21 and Q3 is NHC(O)CH2.
  • Z 3 is O(CH 2 ) j2 C(O) and Q 3 is NHC(O)CH 2 .
  • Z 3 is C(O)NR 21 and Q 3 is a NHC(O)CH 2 .
  • Z 3 is (CH 2 ) j2 C(O)NR 21 and Q 3 is NHC(O)CH 2 .
  • the Linker–Targeting Ligand has the structure selected from Table N:
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1, and the Linker is selected from L3a– L3v. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1, and the Linker is selected from L3a-L3k. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1, and the Linker is selected from L3m-L3v. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1, and the Linker is selected from L3a-L3e.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1, and the Linker is selected from L3f-L3j. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1, and the Linker is selected from L3k–L3p. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1, and the Linker is selected from L3q- L3v.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L3a– L3v.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L3a- L3k.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L3m-L3v.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L3a-L3e.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L3f-L3j.
  • the present application provides the Degron- Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L3k–L3p.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l, and the Linker is selected from L3q-L3v.
  • the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l
  • the Linker is selected from L3q-L3v.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2, and the Linker is selected from L3a– L3v. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2, and the Linker is selected from L3a-L3k. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2, and the Linker is selected from L3m-L3v. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2, and the Linker is selected from L3a-L3e.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2, and the Linker is selected from L3f-L3j. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2, and the Linker is selected from L3k–L3p. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2, and the Linker is selected from L3q-L3v.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2a or D2b, and the Linker is selected from L3a– L3v.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2a or D2b, and the Linker is selected from L3a-L3k.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2a or D2b, and the Linker is selected from L3m-L3v.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2a or D2b, and the Linker is selected from L3a-L3e. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2a or D2b, and the Linker is selected from L3f-L3j. In one embodiment, the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2a or D2b, and the Linker is selected from L3k–L3p. In one embodiment, the present application provides the Degron- Linker (DL), wherein the Degron is of Formula D2a or D2b, and the Linker is selected from L3q- L3v.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2c or D2d, and the Linker is selected from L3a– L3v.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2c or D2d, and the L r is selected from L3a-L3k.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2c or D2d, and the Linker is selected from L3m-L3v.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2c or D2d, and the Linker is selected from L3a-L3e.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2c or D2d, and the Linker is selected from L3f-L3j.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2c or D2d, and the Linker is selected from L3k–L3p.
  • the present application provides the Degron- Linker (DL), wherein the Degron is of Formula D2c or D2d, and the Linker is selected from L3q- L3v.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2e or D2f, and the Linker is selected from L3a– L3v.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2e or D2f, and the Linker is selected from L3a-L3k.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2e or D2f, and the Linker is selected from L3m-L3v.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2e or D2f, and the Linker is selected from L3a-L3e.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2e or D2f, and the Linker is selected from L3f-L3j.
  • the present application provides the Degron-Linker (DL), wherein the Degron is of Formula D2e or D2f, and the Linker is selected from L3k–L3p.
  • the present application provides the Degron- Linker (DL), wherein the Degron is of Formula D2e or D2f, and the Linker is selected from L3q- L3v.
  • the Linker is designed and optimized based on SAR (structure- activity relationship) and X-ray crystallography of the Targeting Ligand with regard to the location of attachment for the Linker.
  • the optimal Linker length and composition vary by the Targeting Ligand and can be estimated based upon X-ray structure of the Targeting Ligand bound to its target.
  • Linker length and composition can be also modified to modulate metabolic stability and pharmacokinetic (PK) and pharmacodynamics (PD) parameters.
  • Some embodiments of present application relate to the Degron-Linkers (DL) having one of the following structures in Table B:
  • Some of the foregoing compounds can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, such as stereoisomers and/or diastereomers.
  • compounds of the application may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers.
  • the compounds of the application are enantiopure compounds.
  • mixtures of stereoisomers or diastereomers are provided.
  • certain compounds, as described herein, may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated.
  • the application additionally encompasses the compounds as individual Z/E isomers substantially free of other E/Z isomers and alternatively, as mixtures of various isomers.
  • the present application provides compounds that target proteins, such as BRD9 for degradation, which have numerous advantages, such as protein activity, over inhibitors of protein function and can a) overcome resistance in certain cases; b) prolong the kinetics of drug effect by destroying the protein, thus requiring resynthesis of the protein even after the compound has been metabolized; c) target all functions of a protein at once rather than a specific catalytic activity or binding event; d) expand the number of drug targets by including all proteins that a ligand can be developed for, rather than proteins whose activity can be affected by a small molecule inhibitor, antagonist or agonist; and e) have increased potency compared to inhibitors due to the possibility of the small molecule acting catalytically.
  • target proteins such as BRD9 for degradation
  • Some embodiments of the present application relate to degradation or loss of 30% to 100% of the target protein. Some embodiments relate to the loss of 50-100% of the target protein. Other embodiments relate to the loss of 75-95% of the targeted protein.
  • a bifunctional compound of the present application (e.g., a bifunctional compound of any of the formulae described herein, or selected from any bifunctional compounds described herein) is capable of modulating (e.g., decreasing) the amount of a targeted protein (e.g., BRD9).
  • a bifunctional compound of the present application (e.g., a bifunctional compound of any of the formulae described herein, or selected from any bifunctional compounds described herein) is also capable of degrading a targeted protein (e.g., BRD9) through the UPP pathway.
  • a bifunctional compound of the present application is capable of treating or preventing a disease or disorder in which BRD9 plays a role.
  • a bifunctional compound of the present application e.g., a bifunctional compound of any of the ulae described herein, or selected from any bifunctional compounds described herein
  • Modulation of BRD9 through UPP-mediated degradation by a bifunctional compound of the application, such as those described herein, provides a novel approach to the treatment, prevention, or amelioration of diseases or disorders in which BRD9 plays a role including, but not limited to, cancer and metastasis, inflammation, arthritis, systemic lupus
  • BRD9 erthematosus
  • skin-related disorders pulmonary disorders
  • cardiovascular disease ischemia
  • neurodegenerative disorders liver disease
  • gastrointestinal disorders viral and bacterial infections
  • central nervous system disorders Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and peripheral neuropathy.
  • modulation of BRD9 through UPP-mediated degradation by a bifunctional compound of the application, such as those described herein also provides a new paradigm for treating, preventing, or ameliorating diseases or disorders in which BRD9 is deregulated.
  • a bifunctional compound of any of the formulae described herein, or selected from any bifunctional compounds described herein of the present application is more efficacious in treating a disease or condition or is more capable of treating a disease or condition resistant to the Targeting Ligand than when the Targeting Ligand is administered alone or not bonded to a Linker and a Degron.
  • the disease of condition is cancer.
  • a bifunctional compound of any of the formulae described herein, or selected from any bifunctional compounds described herein of the present application is capable of modulating or decreasing the amount of BRD9, and thus is useful in treating a disease or condition in which BRD9 plays a role.
  • the disease or condition is cancer.
  • the bifunctional compound of the present application that is more efficacious in treating a disease or condition or is more capable of treating a disease or condition resistant to the Targeting Ligand than when the Targeting Ligand is administered alone or not bonded to a Linker and a Degron is more potent in inhibiting the growth of cells or decreasing the viability of cells than the Targeting Ligand when the Targeting Ligand is administered alone or not bonded to a Linker and a Degron.
  • the cells are cancer cells.
  • the bifunctional compound inhibits the growth of cells or decreases the viability of cells at an IC 50 that is lower than the IC 50 of the Targeting Ligand when the Targeting Ligand is admin d alone or not bonded to a Linker and a Degron for inhibiting the growth or decreasing the viability of the cells.
  • the cells are cancer cells.
  • the IC 50 of the bifunctional compound is at most 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 8%, 5%, 4%, 3%, 2%, 1%, 0.8%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the IC 50 of the Targeting Ligand.
  • the IC50 of the bifunctional compound is at most 50%, 40%, 30%, 20%, 10%, 8%, 5%, 4%, 3%, 2%, 1%, 0.8%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the IC 50 of the Targeting Ligand. In one embodiment, the IC50 of the bifunctional compound is at most 30%, 20%, 10%, 8%, 5%, 4%, 3%, 2%, 1%, 0.8%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the IC 50 of the Targeting Ligand.
  • the IC 50 of the bifunctional compound is at most 10%, 8%, 5%, 4%, 3%, 2%, 1%, 0.8%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the IC 50 of the Targeting Ligand. In one embodiment, the IC 50 of the bifunctional compound is at most 5%, 4%, 3%, 2%, 1%, 0.8%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the IC 50 of the Targeting Ligand. In one embodiment, the IC 50 of the bifunctional compound is at most 2%, 1%, 0.8%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the IC 50 of the Targeting Ligand.
  • the IC 50 of the bifunctional compound is at most 1%, 0.8%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the IC 50 of the Targeting Ligand.
  • the bifunctional compound inhibits the growth of cells or decreases the viability of cells at an E max that is lower than the E max of the Targeting Ligand when the Targeting Ligand is administered alone or not bonded to a Linker and a Degron for inhibiting the growth or decreasing the viability of the cells.
  • the cells are cancer cells.
  • the E max of the bifunctional compound is at most 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 8%, 5%, 4%, 3%, 2%, or 1% of the E max of the Targeting Ligand. In one embodiment, the E max of the bifunctional compound is at most 50%, 40%, 30%, 20%, 10%, 8%, 5%, 4%, 3%, 2%, or 1% of the Emax of the Targeting Ligand. In one embodiment, the Emax of the bifunctional compound is at most 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the E max of the Targeting Ligand.
  • the inhibition of BRD9 activity is measured by IC 50 .
  • the inhibition of BRD9 activity is measured by EC50.
  • Potency of the inhibitor can be determined by EC 50 value.
  • a compound with a lower EC 50 value, as determined under substantially similar conditions is a more potent inhibitor relative to a compound with a higher EC 50 value.
  • the substantially similar conditions comprise determining a BRD9-dependent cell proliferation in vitro or in vivo in cells expressing BRD9. Potency of the inhibitor can also be determined by IC 50 value.
  • a compound with a lower IC 50 value, as determined under substantially similar conditions is a more potent inhibitor relative to a compound with a higher IC 50 value.
  • the substantially similar conditions comprise determining a BRD9-dependent cell proliferation, in vitro or in vivo in cells expressing BRD9.
  • the bifunctional compounds of the present application are useful as anticancer agents, and thus may be useful in the treatment of cancer, by effecting tumor cell death or inhibiting the growth of tumor cells.
  • the disclosed anticancer agents are useful in the treatment of cancers and other proliferative disorders, including, but not limited to breast cancer, cervical cancer, colon and rectal cancer, leukemia, lung cancer, non-small cell lung cancer, melanoma, multiple myeloma, non- Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemias, including but not limited to myeloid, lymphocytic, myelocytic and lymphoblastic leukemias, malignant melanomas, and T-cell lymphoma.
  • A“selective BRD9 inhibitor,” can be identified, for example, by comparing the ability of a compound to inhibit BRD9 protein activity to its ability to inhibit other bromodomain proteins. For example, a substance may be assayed for its ability to inhibit BRD9 protein activity, as well as BRD1, BRD4, and/or BRD7, and/or other bromodomains. In some embodiments, the selectivity can be identified by measuring the EC 50 or IC 50 of the compounds. Definitions
  • alkyl refers to saturated, straight or branched-chain hydrocarbon radicals containing, in certain embodiments, between one and six carbon atoms.
  • C1-C3 alkyl includes methyl, ethyl, n-propyl, and isopropyl.
  • C1-C6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert- butyl, neopentyl, and n-hexyl radicals.
  • alkoxy refers to an -O-alkyl radical.
  • C 1 -C 3 alkoxy includes methoxy, ethoxy, n-propoxy, and isopropoxy.
  • Examples of C 1 -C 6 alkyl radicals include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy, and n-hexoxy radicals.
  • hal halo
  • halogen refer to an atom selected from fluorine, chlorine, bromine and iodine.
  • aryl refers to a mono- or poly-cyclic carbocyclic ring system having one or more aromatic rings, fused or non-fused, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • aralkyl refers to an alkyl residue attached to an aryl ring. Examples include, but are not limited to, benzyl, phenethyl and the like.
  • cycloalkyl denotes a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compound.
  • C 3 -C 8 cycloalkyl examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of C 3 -C 12 -cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.
  • a monovalent group derived from a monocyclic or polycyclic carbocyclic ring compound having at least one carbon-carbon double bond by the removal of a single hydrogen atom examples include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.
  • heteroaryl refers to a mono- or poly-cyclic (e.g., bi-, or tri- cyclic or more) fused or non-fused, radical or ring system having at least one aromatic ring, having from five to ten ring atoms of which one ring atoms is selected from S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon.
  • mono- or poly-cyclic e.g., bi-, or tri- cyclic or more fused or non-fused, radical or ring system having at least one aromatic ring, having from five to ten ring atoms of which one ring atoms is selected from S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon.
  • Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like.
  • heteroarylkyl refers to an alkyl residue attached to a heteroaryl ring. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl and the like.
  • heterocyclyl refers to a non- aromatic 3-, 4-, 5-, 6- or 7-membered ring or a bi- or tri-cyclic group fused of non-fused system, where (i) each ring contains between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, and (iv) the nitr heteroatom may optionally be quaternized.
  • heterocycloalkyl groups include, but are not limited to, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • alkylamino refers to a group having the structure -NH(C 1 -C 12 alkyl), e.g., - NH(C1-C6 alkyl), where C1-C12 alkyl is as previously defined.
  • dialkylamino refers to a group having the structure -N(C 1 -C 12 alkyl) 2 , e.g., -NH(C1-C6 alkyl), where C1-C12 alkyl is as previously defined.
  • acyl includes residues derived from acids, including but not limited to carboxylic acids, carbamic acids, carbonic acids, sulfonic acids, and phosphorous acids.
  • Examples include aliphatic carbonyls, aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic phosphates and aliphatic phosphates.
  • Examples of aliphatic carbonyls include, but are not limited to, acetyl, propionyl, 2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.
  • any of the aryls, substituted aryls, heteroaryls and substituted heteroaryls described herein, can be any aromatic group.
  • Aromatic groups can be substituted or unsubstituted.
  • hal refers to an atom selected from fluorine, chlorine, bromine and iodine.
  • compounds of the application may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the application.
  • substituents such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the application.
  • phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.”
  • substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • substituent may be either the same or different at every position.
  • -NHC(NH)-heteroaryl -NHC(NH)-heterocy kyl, -C(NH)NH-C 1 -C 12 -alkyl, -C(NH)NH-C 2 -C 12 -alkenyl, -C(NH)NH-C 2 -C 12 -alkenyl, C(NH)NH-C 3 -C 12 -cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NHheterocycloalkyl,
  • cancer includes, but is not limited to, the following cancers: epidermoid Oral: buccal cavity, lip, tongue, mouth, pharynx; Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;
  • Gastrointestinal esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel or small intestines (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel or large intestines (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colon-rectum, colorectal, rectum; Genitourinary tract: kidney (
  • uterus endometrial carcinoma
  • cervix cervical carcinoma, pre-tumor cervical dysplasia
  • ovaries ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,
  • adenocarcinoma, fibrosarcoma, melanoma), vagina clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast; Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) hairy cell; lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psorias
  • BBD9 refers to bromodomain-containing protein 9.
  • subject refers to a mammal.
  • a subject therefore refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, and the like.
  • the subject is a human.
  • the subject may be referred to herein as a patient.
  • Treating refers to a method of alleviating or abating a disease and/or its attendant symptoms.
  • “preventing” or“prevent” describes reducing or eliminating the onset of the symptoms or complications of the disease, condition or disorder.
  • target protein(s) is used interchangeably with“target protein(s)”, unless the context clearly dictates otherwise.
  • a“targeted protein” is BRD9.
  • the terms“disease(s)”,“disorder(s)”, and“condition(s)” are used interchangeably, unless the context clearly dictates otherwise.
  • terapéuticaally effective amount of a bifunctional compound or pharmaceutical composition of the application means a sufficient amount of the bifunctional compound or pharmaceutical composition so as to decrease the symptoms of a disorder in a subject.
  • a therapeutically effective amount of a bifunctional compound or pharmaceutical composition of this application will be at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present application will be decided by the attending physician within the scope of sound medical judgment.
  • the specific inhibitory dose for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • the term "pharmaceutically acceptable salt” refers to those salts of the compounds formed by the process of the present application which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are
  • salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the application, or separately by reacting the free base or acid function with a suitable acid or base.
  • salts include, but are not limited to, nontoxic acid addition salts: salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid.
  • pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate,
  • ethanesulfonate formate, fumarate, glucohe te, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • ester refers to esters of the bifunctional compounds formed by the process of the present application which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the bifunctional compounds formed by the process of the present application which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present application.
  • Prodrug means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to afford any compound delineated by the formulae of the instant application.
  • prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol.4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.
  • compositions containing, and methods of treating disorders through administering, pharmaceutically acceptable prodrugs of bifunctional compounds of the application can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two, three, or four amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the application.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and
  • phosphoryloxymethyloxy carbonyls as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
  • Prodrugs of this type are described in J. Med. Chem.1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • the application also provides for a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a bifunctional compound of the application, or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the application provides a kit comprising a bifunctional compound capable of inhibiting BRD9 activity selected from one or more compounds disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, optionally in combination with a second agent and instructions for use in treating cancer.
  • a bifunctional compound capable of inhibiting BRD9 activity selected from one or more compounds disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, optionally in combination with a second agent and instructions for use in treating cancer.
  • the application provides a method of synthesizing a bifunctional compound disclosed herein.
  • inventions are a method of making a bifunctional compound of any of the formulae herein using any one, or combination of, reactions delineated herein.
  • the method can include the use of one or more intermediates or chemical reagents delineated herein.
  • Another aspect is an isotopically labeled bifunctional compound of any of the formulae delineated herein.
  • Such compounds have one or more isotope atoms which may or may not be radioactive, including but not limited to 3 H, 2 H, 14 C, 13 C, 18 F, 35 S, 32 P, 125 I, and 131 I introduced into the bifunctional compound.
  • isotope atoms which may or may not be radioactive, including but not limited to 3 H, 2 H, 14 C, 13 C, 18 F, 35 S, 32 P, 125 I, and 131 I introduced into the bifunctional compound.
  • Such compounds are useful for drug metabolism studies and diagnostics, as well as therapeutic applications.
  • a bifunctional compound of the application can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of a bifunctional compound of the application can be prepared by reacting the free acid form of the bifunctional compound with a pharmaceutically acceptable inorganic or organic base.
  • the salt forms of the bifunctional compounds of the application can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the bifunctional compounds of the application can be prepared from the corresponding base addition salt or acid addition salt from, respectively.
  • a bifunctional compound of the application in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base, including but not limited to ammonium hydroxide solution, sodium hydroxide.
  • a bifunctional compound of the application in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid, including but not limited to hydrochloric acid.
  • Prodrugs of the bifunctional compounds of the application can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p.1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized bifunctional compound of the application with a suitable carbamylating agent, including but not limited to 1,1- acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate.
  • Hydrates of bifunctional compounds of the present application can be conveniently prepared by recrystallization from an
  • aqueous/organic solvent mixture using organic solvents such as dioxin, tetrahydrofuran or methanol.
  • Acids and bases useful in the methods herein are known in the art.
  • Acid catalysts are any acidic chemical, which can be inorganic, including but not limited to hydrochloric, sulfuric, nitric acids, aluminum trichloride or organic, including but not limited to
  • Acids are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions.
  • Bases are any basic chemical, which can be inorganic, including but not limited to sodium bicarbonate, potassium hydroxide or organic, including but not limited to triethylamine, pyridine. Bases are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein, such as therapeutic or prophylactic administration, to a subject.
  • any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence.
  • R 14 at each occurrence is selected independently from the definition of R 14 .
  • combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds within a designated atom’s normal valency.
  • some of the compounds of this application have one or more double bonds, or one or more asymmetric centers.
  • Such compounds can occur as racemates, racemic mixtures, single enantiomers, individual dia omers, diastereomeric mixtures, and cis- or trans- or E- or Z- double isomeric forms, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

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Abstract

La présente invention concerne des composés bifonctionnels de formule (I) : ou un énantiomère, un diastéréomère, ou un stéréo-isomère de ceux-ci un ligand de ciblage (Ib) ou un sel, un hydrate, un solvat, un promédicament pharmaceutiquement acceptable de ceux-ci, qui agissent comme des fragments induisant la dégradation protéique pour la protéine contenant un bromodomaine 9 (BRD9). La présente invention concerne également des procédés de dégradation ciblée de BRD9 en utilisant des composés bifonctionnels qui lient un fragment se liant à l'ubiquitine ligase à un ligand capable de se lier à BRD9 qui peuvent être utilisés dans le traitement des troubles modulés par BRD9.
EP17816295.4A 2016-06-23 2017-06-23 Dégradation de la protéine contenant un bromodomaine 9 (brd9) par conjugaison d'inhibiteurs de brd9 avec un ligand de la ligase e3 et procédés d'utilisation Withdrawn EP3474900A4 (fr)

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CN104736569A (zh) 2012-01-12 2015-06-24 耶鲁大学 通过e3泛素连接酶增强靶蛋白质及其他多肽降解的化合物和方法
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US10633386B2 (en) * 2016-04-12 2020-04-28 The Regents Of The University Of Michigan BET protein degraders

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CA3025806C (fr) 2023-04-04
EP3474900A4 (fr) 2020-03-11
CA3025806A1 (fr) 2017-12-28
AU2017281903A1 (en) 2018-12-13
US20190247509A1 (en) 2019-08-15
AU2017281903B2 (en) 2020-12-24
WO2017223452A1 (fr) 2017-12-28

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